Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as TrkA kinase inhibitors

ABSTRACT

Compounds of Formula I: or stereoisomers, tautomers, or pharmaceutically acceptable salts, or solvates or prodrugs thereof, where R 1 , R 2 , R a , R b , R c , R d , X, Y, B, and Ring C are as defined herein, and wherein the Y—B moiety and the NH—C(═X)—NH moiety are in the trans configuration, are inhibitors of TrkA kinase and are useful in the treatment of diseases which can be treated with a TrkA kinase inhibitor such as pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.

This application is a divisional of U.S. patent application Ser. No.14/117,615, filed on Nov. 13, 2013 and claims priority under 35 U.S.C.119(a) and 35 U.S.C. 365(a) to international patent application numberPCT/US2012/037003, filed May 9, 2012; this application also claimspriority under 35 U.S.C. 119(e) to U.S. Provisional Patent ApplicationNo. 61/485,858 that was filed on May 13, 2011. The entire content of theapplications referenced above are hereby incorporated by referenceherein.

BACKGROUND OF THE INVENTION

The present invention relates to novel compounds, to pharmaceuticalcompositions comprising the compounds, to processes for making thecompounds and to the use of the compounds in therapy. More particularly,it relates to pyrrolidinyl urea and pyrrolidinyl thiourea compoundswhich exhibit TrkA kinase inhibition, and which are useful in thetreatment of pain, cancer, inflammation, neurodegenerative diseases andcertain infectious diseases.

The current treatment regimens for pain conditions utilize severalclasses of compounds. The opioids (such as morphine) have severaldrawbacks including emetic, constipatory and negative respiratoryeffects, as well as the potential for addictions. Non-steroidalanti-inflammatory analgesics (NSAIDs, such as COX-1 or COX-2 types) alsohave drawbacks including insufficient efficacy in treating severe pain.In addition, COX-1 inhibitors can cause ulcers of the mucosa.Accordingly, there is a continuing need for new and more effectivetreatments for the relief of pain, especially chronic pain.

Trk's are the high affinity receptor tyrosine kinases activated by agroup of soluble growth factors called neurotrophins (NT). The Trkreceptor family has three members: TrkA, TrkB and TrkC. Among theneurotrophins are (i) nerve growth factor (NGF) which activates TrkA,(ii) brain-derived neurotrophic factor (BDNF) and NT-4/5 which activateTrkB and (iii) NT3 which activates TrkC. Trk's are widely expressed inneuronal tissue and are implicated in the maintenance, signaling andsurvival of neuronal cells (Patapoutian, A. et al., Current Opinion inNeurobiology, 2001, 11, 272-280).

Inhibitors of the Trk/neurotrophin pathway have been demonstrated to beeffective in numerous pre-clinical animal models of pain. For example,antagonistic NGF and TrkA antibodies such as RN-624 have been shown tobe efficacious in inflammatory and neuropathic pain animal models(Woolf, C. J. et al. (1994) Neuroscience 62, 327-331; Zahn, P. K. et al.(2004) J. Pain 5, 157-163; McMahon, S. B. et al., (1995) Nat. Med. 1,774-780; Ma, Q. P. and Woolf, C. J. (1997) NeuroReport 8, 807-810;Shelton, D. L. et al. (2005) Pain 116, 8-16; Delafoy, L. et al. (2003)Pain 105, 489-497; Lamb, K. et al. (2003) Neurogastroenterol. Motil. 15,355-361; Jaggar, S. I. et al. (1999) Br. J. Anaesth. 83, 442-448) andneuropathic pain animal models (Ramer, M. S. and Bisby, M. A. (1999)Eur. J. Neurosci. 11, 837-846; Ro, L. S. et al. (1999); Herzberg, U. etal., Pain 79, 265-274 (1997) Neuroreport 8, 1613-1618; Theodosiou, M. etal. (1999) Pain 81, 245-255; Li, L. et al. (2003) Mol. Cell. Neurosci.23, 232-250; Gwak, Y. S. et al. (2003) Neurosci. Lett. 336, 117-120).

It has also been shown that NGF secreted by tumor cells and tumorinvading macrophages directly stimulates TrkA located on peripheral painfibers. Using various tumor models in both mice and rats, it wasdemonstrated that neutralizing NGF with a monoclonal antibody inhibitscancer related pain to a degree similar or superior to the highesttolerated dose of morphine. Because TrkA kinase may serve as a mediatorof NGF driven biological responses, inhibitors of TrkA and/or other Trkkinases may provide an effective treatment for chronic pain states.

Recent literature has also shown that overexpression, activation,amplification and/or mutation of Trk kinases are associated with manycancers including neuroblastoma (Brodeur, G. M., Nat. Rev. Cancer 2003,3, 203-216), ovarian (Davidson. B., et al., Clin. Cancer Res. 2003, 9,2248-2259), colorectal cancer (Bardelli, A., Science 2003, 300, 949),melanoma (Truzzi, F., et al., Dermato-Endocrinology 2008, 3 (1), pp.32-36), head and neck cancer (Yilmaz, T., et al., Cancer Biology andTherapy 2010, 10 (6), pp. 644-653), gastric carcinoma (Du, J. et al.,World Journal of Gastroenterology 2003, 9 (7), pp. 1431-1434), lungcarcinoma (Ricci A., et al., American Journal of Respiratory Cell andMolecular Biology 25 (4), pp. 439-446), breast cancer (Jin, W., et al.,Carcinogenesis 2010, 31 (11), pp. 1939-1947), Glioblastoma (Wadhwa, S.,et al., Journal of Biosciences 2003, 28 (2), pp. 181-188),medulloblastoma (Gruber-Olipitz, M., et al., Journal of ProteomeResearch 2008, 7 (5), pp. 1932-1944), secratory breast cancer (Euthus,D. M., et al., Cancer Cell 2002, 2 (5), pp. 347-348), salivary glandcancer (Li, Y.-G., et al., Chinese Journal of Cancer Prevention andTreatment 2009, 16 (6), pp. 428-430), papillary thyroid carcinoma(Greco, A., et al., Molecular and Cellular Endocrinology 2010, 321 (1),pp. 44-49) and adult myeloid leukemia (Eguchi, M., et al., Blood 1999,93 (4), pp. 1355-1363). In preclinical models of cancer, non-selectivesmall molecule inhibitors of Trk A, B and C were efficacious in bothinhibiting tumor growth and stopping tumor metastasis (Nakagawara, A.(2001) Cancer Letters 169:107-114; Meyer, J. et al. (2007) Leukemia,1-10; Pierottia, M. A. and Greco A., (2006) Cancer Letters 232:90-98;Eric Adriaenssens, E., et al. Cancer Res (2008) 68:(2) 346-351).

In addition, inhibition of the neurotrophin/Trk pathway has been shownto be effective in treatment of pre-clinical models of inflammatorydiseases with NGF antibodies or non-selective small molecule inhibitorsof Trk A. For example, inhibition of the neurotrophin/Trk pathway hasbeen implicated in preclinical models of inflammatory lung diseasesincluding asthma (Freund-Michel, V; Frossard, N., Pharmacology &Therapeutics (2008) 117(1), 52-76), interstitial cystitis (Hu Vivian Y;et. al. The Journal of Urology (2005), 173(3), 1016-21), inflammatorybowel diseases including ulcerative colitis and Crohn's disease (DiMola, F. F, et. al., Gut (2000) 46(5), 670-678) and inflammatory skindiseases such as atopic dermatitis (Dou, Y.-C., et. al. Archives ofDermatological Research (2006) 298(1), 31-37), eczema and psoriasis(Raychaudhuri, S. P., et al., J. Investigative Dermatology (2004)122(3), 812-819).

The TrkA receptor is also thought to be critical to the disease processin the infection of the parasitic infection of Trypanosoma cruzi (Chagasdisease) in human hosts (de Melo-Jorge, M. et al., Cell Host & Microbe(2007) 1(4), 251-261).

Trk inhibitors may also find use in treating disease related to animbalance of the regulation of bone remodeling, such as osteoporosis,rheumatoid arthritis, and bone metastases. Bone metastases are afrequent complication of cancer, occurring in up to 70 percent ofpatients with advanced breast or prostate cancer and in approximately 15to 30 percent of patients with carcinoma of the lung, colon, stomach,bladder, uterus, rectum, thyroid, or kidney. Osteolytic metastases cancause severe pain, pathologic fractures, life-threatening hypercalcemia,spinal cord compression, and other nerve-compression syndromes. Forthese reasons, bone metastasis is a serious and costly complication ofcancer. Therefore, agents that can induce apoptosis of proliferatingosteoblasts would be highly advantageous. Expression of TrkA receptorshas been observed in the bone forming area in mouse models of bonefracture (K. Asaumi, et al., Bone (2000) 26(6) 625-633). In addition,localization of NGF was observed in almost all bone forming cells (K.Asaumi, et al.). Recently, it was demonstrated that a Trk inhibitorinhibits the tyrosine signaling activated by neurotrophins binding toall three of the Trk receptors in human hFOB osteoblasts (J. Pinski, etal., (2002) 62, 986-989). These data support the rationale for the useof Trk inhibitors for the treatment of bone remodeling diseases, such asbone metastases in cancer patients.

Several classes of small molecule inhibitors of Trk kinases said to beuseful for treating pain or cancer are known (Expert Opin. Ther. Patents(2009) 19(3), 305-319).

SUMMARY OF THE INVENTION

It has now been found that pyrrolidinyl urea, pyrrolidinyl thiourea andpyrrolidinyl guanidine compounds are inhibitors of TrkA, and may beuseful for treating disorders and diseases such as pain, includingchronic and acute pain. Compounds of the invention may be useful in thetreatment of multiple types of pain including inflammatory pain,neuropathic pain, and pain associated with cancer, surgery, and bonefracture. In addition, compounds of the invention may be useful fortreating cancer, inflammation, neurodegenerative diseases and certaininfectious diseases.

More specifically, provided herein are compounds of Formula I:

or stereoisomers, tautomers, or pharmaceutically acceptable salts,solvates or prodrugs thereof, wherein the Y—B moiety and the NH—C(═X)—NHmoiety are in the trans configuration and R¹, R², R^(a), R^(b), R^(c),R^(d), X, Y, B, and Ring C are as defined herein.

In one embodiment, provided herein are compounds of Formula I′:

or stereoisomers, tautomers, or pharmaceutically acceptable salts,solvates or prodrugs thereof, wherein Ring B and the NH—C(═X)—NH moietyare in the trans configuration and R¹, R², R^(a), R^(b), R^(c), R^(d),X, Ring B, and Ring C are as defined herein.

Another aspect of the present invention provides methods of preventingor treating a disease or disorder modulated by TrkA, comprisingadministering to a mammal in need of such treatment an effective amountof a compound of this invention or a stereoisomer, solvate orpharmaceutically acceptable salt thereof. In one embodiment, the diseaseand disorders include chronic and acute pain, including but not limitedto inflammatory pain, neuropathic pain, and pain associated with cancer,surgery, and bone fracture. In another embodiment, the disease anddisorders include, but are not limited to, cancer, inflammation,neurodegenerative diseases and certain infectious diseases.

Another aspect of the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention or apharmaceutically acceptable salt thereof.

Another aspect of the present invention provides the compounds of thepresent invention for use in therapy.

Another aspect of the present invention provides the compounds of thepresent invention for use in the treatment of disease and disorders ofchronic and acute pain, including but not limited to inflammatory pain,neuropathic pain, and pain associated with cancer, surgery, and bonefracture. Another aspect of the present invention provides the compoundsof the present invention for use in the treatment of disease anddisorders selected from cancer, inflammation, neurodegenerative diseasesand certain infectious diseases.

Another aspect of the present invention provides the use of a compoundof this invention in the manufacture of a medicament for the treatmentof disease and disorders such as chronic and acute pain including, butnot limited to, inflammatory pain, neuropathic pain, and pain associatedwith cancer, surgery, and bone fracture.

Another aspect of the present invention provides the use of a compoundof this invention in the manufacture of a medicament for the treatmentof disease and disorders selected from cancer, inflammation,neurodegenerative diseases and certain infectious diseases.

Another aspect of the present invention provides intermediates forpreparing compounds of Formula I.

Another aspect of the present invention includes methods of preparing,methods of separation, and methods of purification of the compounds ofthis invention.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein are compounds, and pharmaceutical formulations thereof,that are potentially useful in the treatment of diseases, conditionsand/or disorders modulated by TrkA.

One embodiment provides a compound of Formula I:

or stereoisomers, tautomers, or pharmaceutically acceptable salts,solvates or prodrugs thereof, wherein:

the Y—B moiety and the NH—C(═X)—NH moiety are in the transconfiguration;

R^(a), R^(b), R^(c) and R^(d) are independently selected from H and(1-3C)alkyl;

X is O, S or NH;

R¹ is (1-3C alkoxy)(1-6C)alkyl, (trifluoromethoxy)(1-6C)alkyl, (1-3Csulfanyl)(1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluro(2-6C)alkyl,cyano(1-6C)alkyl, aminocarbonyl(1-6C)alkyl, hydroxy(1-6C)alkyl,dihydroxy(2-6C)alkyl, (1-6C)alkyl, (1-3Calkylamino)(1-3C)alkyl, (1-4Calkoxycarbonyl)(1-6C)alkyl, amino(1-6C)alkyl, hydroxy(1-3Calkoxy)(1-6C)alkyl, di(1-3C alkoxy)(1-6C)alkyl, (1-3Calkoxy)trifluoro(1-6C)alkyl, hydroxytrifluoro(1-6C)alkyl, (1-4Calkoxycarbonyl)(1-3C alkoxy)(1-6C)alkyl, hydroxycarbonyl(1-3Calkoxy)(1-6C)alkyl, hetAr⁵(CH₂)₀₋₁, or Ar⁵(CH₂)₀₋₁;

R² is H, F, or OH;

Y is a bond, —O— or —OCH₂—;

B is Ar¹, hetAr¹, 1-6C alkyl or (1-6C)alkoxy;

Ar¹ is phenyl optionally substituted with one or more substituentsindependently selected from halogen, CF₃, CF₃O—, (1-4C)alkoxy,hydroxy(1-4C)alkyl, (1-6C)alkyl and CN;

hetAr¹ is a 5-6 membered heteroaryl having 1-3 ring heteroatomsindependently selected from N, S and O, and optionally substituted with1-2 groups independently selected form (1-6C)alkyl, halogen, OH, CF₃,NH₂ and hydroxy(1-2C)alkyl;

Ring C is formula C-1, C-2, or C-3

R³ is H, (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar², hetCyc¹,(3-7C)cycloalkyl, or hetAr²;

Ar² is phenyl optionally substituted with one or more groupsindependently selected from halogen, (1-6C)alkyl and hydroxymethyl;

hetCyc¹ is a 5-6-membered saturated or partially unsaturatedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O;

hetAr² is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S and optionally substituted withone or more groups independently selected from (1-6C)alkyl and halogen;

R⁴ is H, OH, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl,cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl,(1-3C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl,hydroxycarbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar³(1-6C)alkyl,(1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy trifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxycyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy,amino(2-6C)alkoxy, aminocarbonyl(1-6C)alkoxy,hydroxyl-carbonyl(1-6C)alkoxy, hetCyc²(1-6C)alkoxy, hetAr³(1-6C)alkoxy,Ar³(1-6C)alkoxy, (1-4C alkoxy) (1-6C)alkoxy, (1-3Calkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [optionally substitutedwith F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(1-6C)alkyl],hetAr⁴, Ar⁴, hetCyc²(O)CH₂—, (1-4C alkoxycarbonyl)(1-6C)alkoxy,hydroxycarbonyl(1-6C)alkoxy, aminocarbonyl(1-6C)alkoxy,hetCyc²C(═O)(1-6C)alkoxy, hydroxy(1-3C alkoxy)(1-6C)alkoxy,hydroxytrifluoro(1-6C)alkoxy, (1-3C)alkylsulfonamido(1-6C)alkoxy,(1-3C)alkylamido(1-6C)alkoxy, di(1-3C alkyl)aminocarboxy,hetCyc²C(═O)O—, hydroxydifluoro(1-6C)alkyl, (1-4Calkylcarboxy)(1-6C)alkyl, (1-6C)alkoxycarbonyl, hydroxyl/carbonyl,aminocarbonyl, (1-3C alkoxy)aminocarbonyl, hetCyc³, halogen, CN,trifluoromethylsulfonyl, N-(1-3C alkyl)pyridinonyl, N-(1-3Ctrifluoroalkyl) pyridinonyl, (1-4C alkylsiloxy)(1-6C)alkoxy,isoindoline-1,3-dionyl(1-6C)alkoxy or N-(1-3C alkyl)oxadiazolonyl;

hetCyc² is a 4-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with 1-2groups independently selected from (1-6C)alkyl, (1-4Calkylcarboxy)(1-6C)alkyl, and (1-6C)acyl;

hetCyc³ is a 4-7 membered heterocycle having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with oneor more substituents independently selected from F, CN, CF₃,(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C) acyl-,(1-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl;

hetAr³ is a 5-membered heteroaryl ring having 1-3 ring atomsindependently selected from N, O and S and optionally substituted with(1-6C)alkyl;

Ar³ is phenyl optionally substituted with (1-4C)alkoxy;

hetAr⁴ is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, S and O and optionally substituted with1-2 substituents independently selected from (1-6C)alkyl, halogen, CN,hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH₂-(3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino, (1-3C trifluoroalkoxy), (1-3C)trifluoroalkyl, andmethoxybenzyl; or a 9-10 membered bicyclic heteroaryl having 1-3 ringnitrogen atoms;

Ar⁴ is phenyl optionally substituted with one or more groupsindependently selected from (1-6C)alkyl, halogen, CN, CF₃, CF₃O—,(1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio,hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3Calkyl)OC(═O)—;

R⁵ is H, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl,halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl,(1-4C alkyl)OC(═O)—, (1-6C)alkylthio, phenyl [optionally substitutedwith one or more groups independently selected from halogen, (1-6C)alkyland (1-6C)alkoxy], (3-4C)cycloalkyl, amino, aminocarbonyl, ortrifluoro(1-3C alky)amido; or

R⁴ and R⁵ together with the atoms to which they are attached form a 5-6membered saturated, partially unsaturated or unsaturated carbocyclicring optionally substituted with one or more substituents independentlyselected from (1-6C)alkyl, or

R⁴ and R⁵ together with the atoms to which they are attached form 5-6membered saturated, partially unsaturated or unsaturated heterocyclicring having a ring heteroatom selected from N, O or S, wherein saidheterocyclic ring is optionally substituted with one or two substituentsindependently selected from (1-6C alkyl)C(═O)O—, (1-6)acyl, (1-6C)alkyland oxo, and said sulfur ring atom is optionally oxidized to S(═O) orSO₂;

hetAr⁵ is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O or S, wherein the ring is optionallysubstituted with one or more substituents independently selected fromhalogen, (1-6C)alkyl, (1-6C)alkoxy and CF₃;

Ar⁵ is phenyl optionally substituted with one or more groupsindependently selected from halogen, (1-6C)alkyl, (1-6C)alkoxy, CF₃O—,(1-4C)alkoxycarbonyl and aminocarbonyl;

R^(3a) is hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl,(3-6C)cycloalkyl, phenyl optionally substituted with one or moresubstituents independently selected from halogen, (1-6C)alkyl andhydroxymethyl, or a 5-6 membered heteroaryl ring having 1-3 ringheteroatoms independently selected from N, O and S and optionallysubstituted with one or more groups independently selected from(1-6C)alkyl and halogen;

R^(3b) is hydrogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl,phenyl optionally substituted with one or more substituentsindependently selected from halogen, (1-6C)alkyl and hydroxymethyl, or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, O and S and optionally substituted with one or moregroups independently selected from (1-6C)alkyl and halogen;

R^(4a) is hydrogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, phenyl[optionally substituted with one or more groups independently selectedfrom (1-6C)alkyl, halogen, CN, CF₃, CF₃O—, (1-6C)alkoxy,(1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl,(1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—], or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, S and O and optionally substituted with 1-2substituents independently selected from (1-6C)alkyl,hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH₂-(3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino, (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl, andmethoxybenzyl; and

R^(5a) is hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl,(3-6C)cycloalkyl, phenyl optionally substituted with one or moresubstituents independently selected from halogen, (1-6C)alkyl andhydroxymethyl, or a 5-6 membered heteroaryl ring having 1-3 ringheteroatoms independently selected from N, O and S and optionallysubstituted with one or more groups independently selected from(1-6C)alkyl and halogen.

In one embodiment, compounds of Formula I have the structure I′:

or stereoisomers, tautomers, or pharmaceutically acceptable salts,solvates or prodrugs thereof, wherein:

Ring B and the NH—C(═X)—NH moiety are in the trans configuration;

R^(a), R^(b), R^(c) and R^(d) are independently selected from H and(1-3C)alkyl;

X is O or S;

R¹ is (1-3C alkoxy)(1-6C)alkyl, (trifluoromethoxy)(1-6C)alkyl, (1-3Csulfanyl)(1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluro(2-6C)alkyl,cyano(1-6C)alkyl, aminocarbonyl(1-6C)alkyl, hydroxy(1-6C)alkyl,dihydroxy(2-6C)alkyl, (1-6C)alkyl, or (1-3 Calkylamino)(1-3C)alkyl;

R² is H, F, or OH;

Ring B is Ar¹ or hetAr¹;

Ar¹ is phenyl optionally substituted with one or more substituentsindependently selected from halogen, CF₃, CF₃O—, (1-4C)alkoxy,hydroxy(1-4C)alkyl and (1-6C)alkyl;

hetAr¹ is a 5-6 membered heteroaryl having 1-3 ring heteroatomsindependently selected from N, S and O, and optionally substituted with1-2 groups independently selected form (1-6C)alkyl, halogen, OH, CF₃,NH₂ and hydroxy(1-2C)alkyl;

Ring C is

R³ is H, (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar², hetCyc¹,(3-7C)cycloalkyl, or hetAr²;

Ar² is phenyl optionally substituted with one or more groupsindependently selected from halogen, (1-6C)alkyl and hydroxymethyl;

hetCyc¹ is a 5-6-membered saturated or partially unsaturatedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O;

hetAr² is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S and optionally substituted with(1-6C)alkyl;

R⁴ is H, OH, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl,cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl,(1-3C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl,hydroxycarbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar³(1-6C)alkyl,(1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy,trifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxycyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy,amino(2-6C)alkoxy, aminocarbonyl(1-6C)alkoxy,hydroxycarbonyl(1-6C)alkoxy, hetCyc²(1-6C)alkoxy, hetAr³(1-6C)alkoxy,Ar³(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3Calkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr⁴, or Ar⁴;

hetCyc² is a 4-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with 1-2groups independently selected from (1-6C)alkyl;

hetAr³ is a 5-membered heteroaryl ring having 1-3 ring atomsindependently selected from N, O and S and optionally substituted with(1-6C)alkyl;

Ar³ is phenyl optionally substituted with (1-4C)alkoxy;

hetAr⁴ is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, S and O and optionally substituted with1-2 substituents independently selected from (1-6C)alkyl, or a 9-10membered bicyclic heteroaryl having 1-3 ring nitrogen atoms;

Ar⁴ is phenyl optionally substituted with one or more groupsindependently selected from (1-6C)alkyl, halogen, CN, CF₃, CF₃O—,(1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio,hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3Calkyl)OC(═O)—; and

R⁵ is H, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl,halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl,(1-4C alkyl)OC(═O)—, (1-6C)alkylthio, or phenyl optionally substitutedwith one or more groups independently selected from halogen, (1-6C)alkyland (1-6C)alkoxy; or

R⁴ and R⁵ together with the atoms to which they are attached form a 5-6membered saturated carbocyclic ring optionally substituted with one ormore substituents independently selected from (1-6C)alkyl, or

R⁴ and R⁵ together with the atoms to which they are attached form a 5-6membered saturated heterocyclic ring having a ring heteroatom selectedfrom N, O or S, wherein said ring nitrogen atom is optionallysubstituted with (1-6C alkyl)C(═O)O— or (1-6)acyl, and said sulfur ringatom is optionally oxidized to S(═O) or SO₂.

It is to be understood that in instances where two or more radicals areused in succession to define a substituent attached to a structure, thefirst named radical is considered to be terminal and the last namedradical is considered to be attached to the structure in question. Thus,for example, the radical “alkoxyalkyl” is attached to the structure inquestion by the alkyl group.

The terms “(1-6C)alkyl”, “(1-4C)alkyl” and “(1-3C)alkyl” as used hereinrefer to saturated linear monovalent hydrocarbon radicals of one to sixcarbon atoms, one to four carbon atoms, and one to three carbon atoms,respectively, or a branched saturated monovalent hydrocarbon radical ofthree to six carbon atoms, three to four carbon atoms, or three carbonatoms, respectively. Examples include, but are not limited to, methyl,ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl,2-methyl-2-propyl, 2,2-dimethylpropyl, 1-pentyl, 2-pentyl, 3-pentyl,2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl,1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl,2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

“(1-4C)Alkoxy”, “(1-3C)alkoxy”, “(1-6C)alkoxy” and “(2-6C)alkoxy” referto an —OR radical where R is (1-4C)alkyl, (1-3C)alkyl, (1-6C)alkyl, or(2-6C)alkyl, respectively, as defined above. Examples include methoxy,ethoxy, and the like.

“(1-6)Acyl” means a RC(═O)— radical where R is a linear saturatedmonovalent hydrocarbon radical of one to five carbon atoms or a branchedsaturated monovalent hydrocarbon radical of three to five carbon atoms,e.g., methylcarbonyl, and the like.

“(1-3C Alkoxy)(1-6C)alkyl” and “(1-3C alkoxy)(1-4C)alkyl” mean a linearsaturated monovalent hydrocarbon radical of one to six carbon atoms orone to four carbon atoms, or a branched saturated monovalent hydrocarbonradical of three to six carbon atoms or three to four carbon atoms,respectively, wherein one of the carbon atoms is substituted with one(1-3C)alkoxy group as defined herein.

“(1-3C Alkoxy)(1-6C)alkoxy” means a (1-6C)alkoxy group as definedherein, wherein one of the carbon atoms is substituted with a(1-3C)alkoxy group as defined herein. Examples include methoxymethoxy,methoxyethoxy, and the like.

“(1-3C Alkoxy)aminocarbonyl” means a (1-3C alkyl)-O—NH—C(═O)— group.

“(1-6C)Alkoxycarbonyl” and “(1-4C)alkoxycarbonyl” mean a (1-6C)—O—C(═O)—and (1-4C)—O—C(═O)— group, respectively.

(1-4C Alkoxycarbonyl)(1-6C)alkyl means a (1-6C)alkyl group as definedherein, wherein one of the carbons is substituted with a (1-4Calkoxy)carbonyl group as defined herein.

“(1-3C Alkoxy)trifluoro(1-6C)alkyl” means a (1-6C)alkyl group as definedherein, wherein one of the carbons is substituted with three fluoros,and another carbon is substituted with a (1-3C)alkoxy group as definedherein.

“(1-4C Alkoxycarbonyl)(1-6C alkoxy)” means a (1-6C) alkoxy group asdefined herein wherein one of the carbon atoms is substituted with one(1-4C alkoxycarbonyl group, i.e., an alkyl-O—C(═O)— group.

“(1-4C Alkoxycarbonyl)(1-3C alkoxy)(1-6C)alkyl” means a (1-3Calkoxy)(1-6C)alkyl group as defined herein wherein one of the carbonatoms is substituted with one (1-4C alkoxycarbonyl group, i.e., analkyl-O—C(═O)— group.

“(1-3C Alkoxy)hydroxycarbonylalkyl” means a hydroxycarbonylalkyl groupas defined herein wherein one of the carbon atoms is substituted withone (1-3C alkoxy) group.

“Amino” means a —NRR′ group where R and R′ are independently selectedfrom hydrogen or (1-3C)alkyl as defined herein. Examples include H₂N—,CH₃NH—, (CH₃)₂N, and the like.

“Amino(1-6C)alkyl” means a linear saturated monovalent hydrocarbonradical of one to six carbon atoms or a branched saturated monovalenthydrocarbon radical of three to six carbon atoms, wherein one of thecarbon atoms is substituted with one —NRR′ group where R and R′ areindependently selected from hydrogen or (1-3C)alkyl as defined herein.Examples include aminomethyl, methylaminoethyl,2-ethylamino-2-methylethyl, and the like.

“Amino(2-6C)alkoxy” means a (2-6C)alkoxy group as defined herein,wherein one of the carbon atoms is substituted with one —NRR′ groupwhere R and R′ are independently selected from hydrogen or (1-3C)alkylas defined herein.

“Aminocarbonyl” means a RR′NCO— radical where R and R′ are independentlyhydrogen or (1-6C)alkyl as defined herein. Examples include H₂NCO—,dimethylaminocarbonyl, and the like.

“Aminocarbonyl(1-6C)alkyl” means a linear saturated hydrocarbon radicalof one to six carbon atoms or a branched saturated monovalenthydrocarbon radical of three to six carbons wherein one of the carbonatoms is substituted with one aminocarbonyl group as defined herein,e.g., 2-aminocarbonylethyl, 1-, 2-, or 3-dimethylaminocarbonylpropyl,and the like.

“Aminocarbonyl(1-6C)alkoxy” means a (1-6C)alkoxy as defined herein,wherein one of the carbon atoms is substituted with one aminocarbonylgroup as defined herein.

“(1-3C)Alkylamido(1-6C)alkoxy” means a (1-6C)alkoxy as defined herein,wherein one of the carbon atoms is substituted with one alkylaminogroup, i.e., substituted with a (1-3C)C(═O)NH— group.

“(1-4C alkyl)carboxy” means a R′—C(═O)O— group where R′ is (1-4C)alkyl.

“(1-4C alkylsiloxy)(1-6C)alkoxy” means a (1-6C)alkoxy group as definedherein wherein one of the carbon atoms is substituted with one (1-4Calkyl)siloxy group, e.g., a (1-4C alkyl)Si—O— group such as atert-butylsiloxy group.

“(1-3C)Alkylsulfonamido” means a (1-3C)alkylSO₂NH— radical where(1-3C)alkyl is as defined herein

“(1-3C Alkylsulfonamido)(1-6C)alkyl” means a linear saturatedhydrocarbon radical of one to six carbon atoms or a branched saturatedmonovalent hydrocarbon radical of three to six carbons substituted withone (1-3C)alkylsulfonamido group as defined herein.

“(1-3C)Alkylsulfonamido(1-6C)alkoxy” means a (1-6C)alkoxy group asdefined herein wherein one of the carbon atoms is substituted with one(1-3C)alkylsulfonamido group as defined herein.

“(1-3C)Alkylsulfonyl” means a —SO₂R radical where R is (1-3C)alkyl asdefined above, e.g., methylsulfonyl, and the like.

“(1-3C Alkylsulfonyl)(1-6C)alkoxy” means a (1-6C)alkoxy group as definedherein, wherein one of the carbon atoms is substituted with a(1-3C)alkylsulfonyl group.

“Hydroxycarbonyl” means HOC(═O)—.

“(1-4C alkyl)carboxy(1-6C)alkyl” means a (1-6C)alkyl group as definedherein wherein one of the carbon atoms is substituted with a (1-4Calkyl)carboxy group as defined herein.

“Cyano(1-6C)alkyl” means a linear saturated hydrocarbon radical of oneto six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to six carbons substituted with a cyano (CN) group.

“(3-6C)Cycloalkyl” means a cyclic saturated monovalent hydrocarbonradical of three to six carbon atoms, e.g., cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

“Di(1-3C alkoxy)(1-6C)alkyl” means a (1-6C)alkyl group as definedherein, wherein two carbons are each substituted with one (1-3C)alkoxygroup as defined herein.

“Dihydroxy(2-6C)alkyl” means a linear saturated hydrocarbon radical oftwo to six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to six carbons substituted with two hydroxy (OH)groups, provided that two hydroxy groups are not both on the same carbonatom.

“Dihydroxy(2-6C)alkoxy” means a (2-6C)alkoxy group as defined herein,wherein two of the carbon atoms are substituted with a hydroxy group.

“Halogen” as used herein means F, Cl, Br or I.

“Heterocycle” refers to a saturated or partially unsaturated ring systemhaving one or more ring heteroatoms as recited for the specificheterocyclic group, wherein the heterocycle is optionally substitutedwith substituents as defined for that particular heterocyclic group.

“Heteroaryl” refers to a 5-6 membered unsaturated ringsystem having oneor more ring heteroatoms as recited for the specific heteroaryl group,wherein the heteroaryl is optionally substituted with substituents asdefined for that particular heteroaryl group.

“hetCyc²C(═O)(1-6C)alkoxy” means a (1-6C)alkoxy as defined herein,wherein one of the carbon atoms is substituted with a hetCyc²C(═O)group, wherein hetCyc² is as defined herein.

“Hydroxy(1-6C)alkyl” and “hydroxy(1-4C)alkyl” means a linear saturatedhydrocarbon radical of one to six carbon atoms or one to four carbonatoms, respectively, or a branched saturated monovalent hydrocarbonradical of three to six carbon atoms or three to four carbon atoms,respectively, wherein one of the carbon atoms is substituted with ahydroxy (OH) group.

“Hydroxy(1-6C)alkoxy” means a (1-6C)alkoxy group as defined herein,wherein one of the carbon atoms is substituted with a hydroxy group.

“Hydroxy(1-3C alkoxy)(1-6C)alkyl” means a (1-3C alkoxy)(1-6C)alkyl groupas defined herein, wherein one of the carbons is substituted with ahydroxy group.

“Hydroxy(1-3C alkoxy)(1-6C)alkoxy” means a (1-3C alkoxy)(1-6C)alkoxy asdefined herein, wherein one of the carbon atoms is substituted with ahydroxy group.

“Hydroxydifluoro(1-6C)alkyl” means a difluoro(1-6C)alkyl group asdefined herein, wherein one of the carbon atoms is substituted with ahydroxy group.

“Hydroxytrifluoro(1-6C)alkoxy” means a trifluoro(1-6C)alkoxy group asdefined herein, wherein one of the carbon atoms is substituted with ahydroxy group.

“Hydroxycarbonylalkyl” means a linear saturated hydrocarbon radical ofone to six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to six carbons substituted with one —COOH group.Examples include 2-hydroxycarbonylethyl, 1-, 2-, or3-hydroxycarbonylpropyl, and the like.

“Isoindoline-1,3-dionyl(1-6C)alkoxy” means a (1-6C)alkoxy group asdefined herein, wherein one of the carbon atoms is substituted with anisoindoline-1,3-dionyl group.

“Monofluoro(1-6C)alkyl”, “difluoro(1-6C)alkyl” and“trifluoro(1-6C)alkyl” refer to a (1-6C)alkyl group as defined hereinwherein one to three hydrogen atoms, respectively, is replaced by afluoro group.

“Tetrafluoro(2-6C)alkyl” and “pentafluoro(2-6C)alkyl” refer to a linearsaturated monovalent hydrocarbon radical of two to six carbon atoms or abranched saturated monovalent hydrocarbon radical of three to six carbonatoms wherein four to five hydrogen atoms, respectively, is replaced bya fluoro group.

“(Trifluoromethoxy)(1-6C)alkyl” means a linear saturated hydrocarbonradical of one to six carbon atoms or a branched saturated monovalenthydrocarbon radical of three to six carbons substituted with one CF₃O—group.

“Trifluoro(1-3C alky)amido” means a (1-3C alkyl)C(═O)NH— group whereinone of the carbons is substituted with three fluoros.

“Trifluoro(1-6C)alkoxy” means a (1-6C)alkoxy group as defined herein,wherein one of the carbon atoms is substituted with three fluoros.

“Sulfamido(1-6C)alkyl” means a linear saturated hydrocarbon radical ofone to six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to six carbons substituted with one sulfamido(H₂NSO₂NH—) group.

It should be noted that compounds of the invention may contain groupsthat may exist in tautomeric forms, such as heteroatom substitutedheteroaryl or heterocyclic groups and the like, which are illustrated inthe following general and specific examples:

where Y′=O, S, or NR, and though one form is named, described, displayedand/or claimed herein, all the tautomeric forms are intended to beinherently included in such name, description, display and/or claim.

In one embodiment of Formula I, R^(a), R^(b), R^(c) and R^(d) areindependently selected from H and methyl. In one embodiment, R^(a),R^(b), R^(c) and R^(d) are hydrogen. In one embodiment, R^(a) is methyland R^(b), R^(c) and R^(d) are hydrogen. In one embodiment, R^(a) andR^(b) are methyl and R^(c) and R^(d) are hydrogen. In one embodiment,R^(a), R^(b) and R^(c) are hydrogen and R^(d) is methyl. In oneembodiment, R^(a) and R^(b) are hydrogen and R^(c) and R^(d) are methyl.

In one embodiment, X is O.

In one embodiment, X is S.

In one embodiment, X is NH.

In one embodiment, R¹ is (1-3C alkoxy)(1-6C)alkyl, for example,methoxyethyl, methoxypropyl, ethoxyethyl and 2-methoxypropyl. Particularexamples include methoxyethyl and 2-methoxypropyl having the structures:

In one embodiment, R¹ is (trifluoromethoxy)(1-6C)alkyl, for example,trifluoromethoxyethyl, trifluoromethoxypropyl, and the like. Aparticular example is trifluoromethoxyethyl.

In one embodiment, R¹ is (1-3C sulfanyl)(1-6C)alkyl, for examplemethylsulfanylethyl, ethylsulfanylethyl, and the like. A particularexample is methylsulfanylethyl.

In one embodiment, R¹ is monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl ortrifluoro(1-6C)alkyl. Particular examples include 1,3-difluoroprop-2-yl,2,2-difluoroethyl 2,2,2-trifluoroethyl and 2,2,2-trifluoropropyl havingthe structures:

In one embodiment, R¹ is tetrafluoro(2-6C)alkyl orpentafluoro(2-6C)alkyl. A particular example is3,3,4,4,4-pentafluorobutyl.

In one embodiment, R¹ is cyano(1-6C)alkyl. A particular example is2-cyanoethyl.

In one embodiment, R¹ is aminocarbonyl(1-6C)alkyl. A particular exampleis aminocarbonylmethyl. Another example is methylaminocarbonylmethylhaving the formula MeNHC(═O)CH₂—.

In one embodiment, R¹ is hydroxy(1-6C)alkyl. A particular example is2-hydroxyethyl. Another example is 2-hydroxypropyl.

In one embodiment, R¹ is dihydroxy(2-6C)alkyl. A particular example isthe structure:

In one embodiment, R¹ is (1-6C)alkyl. Examples include methyl, ethyl,and propyl.

In one embodiment, R¹ is (1-3Calkylamino)(1-3C)alkyl, that is, a(1-3C)alkyl group which is substituted with a (1-3C alkyl)amino group,for example a (1-3Calkyl)NH— group such as methylamino. A particularexample is (2-methylamino)ethyl.

In one embodiment, R¹ is (1-4C alkoxycarbonyl)(1-6C)alkyl. A particularexample is methoxycarbonylmethyl, having the structure:

In one embodiment, R¹ is amino(1-6C)alkyl, such asmethylamino(1-6C)alkyl. A particular example is 2-methylaminoethyl.

In one embodiment, R¹ is hydroxy(1-3C alkoxy)(1-6C)alkyl. Examplesinclude hydroxymethoxy(1-6C)alkyl. Particular examples include thestructures:

In one embodiment, R¹ is di(1-3C alkoxy)(1-6C)alkyl. Examples includedimethoxy(1-6C)alkyl. A particular example includes1,3-dimethoxyprop-2-yl having the structure:

In one embodiment, R¹ is (1-3C alkoxy)trifluoro(1-6C)alkyl. Examplesinclude methoxytrifluoro(1-6C)alkyl. A particular example includes3,3,3-trifluoro-2-methoxypropyl.

In one embodiment, R¹ is hydroxytrifluoro(1-6C)alkyl. A particularexample includes 3,3,3-trifluoro-2-hydroxypropyl.

In one embodiment, R¹ is (1-4C alkoxycarbonyl)(1-3C alkoxy)(1-6C)alkyl.Examples include (methoxycarbonyl)methoxy(1-6C)alkyl. A particularexample includes the structure:

In one embodiment, R¹ is hydroxycarbonyl(1-3C alkoxy)(1-6C)alkyl.Examples include (methoxycarbonyl)hydroxy(1-6C)alkyl. A particularexample includes the structure:

In one embodiment, R¹ is hetAr⁵(CH₂)₀₋₁.

In one embodiment, R¹ is hetAr⁵, where hetAr⁵ is a 5-6 memberedheteroaryl ring having 1-3 ring heteroatoms independently selected fromN, O or S, wherein the ring is optionally substituted with one or moresubstituents independently selected from halogen, (1-6C)alkyl,(1-6C)alkoxy and CF₃. Examples include pyrrolyl, pyrazolyl, imidazolyl,furanyl, isoxazolyl, oxazolyl, thiophenyl, thiazolyl, thiadiazolyl,triazolyl, thiadiazolyl, pyridyl, pyrimidyl and pyrazinyl rings, whereinthe ring is optionally substituted with one or more substituentsindependently selected from halogen, (1-6C)alkyl, (1-6C)alkoxy and CF₃.

In one embodiment, R¹ is hetAr⁵, where herAr⁵ is pyrazolyl, pyridyl orpyrazinyl optionally substituted with one or more one or moresubstituents independently selected from halogen, (1-6C)alkyl,(1-6C)alkoxy and CF₃. In one embodiment, herAr⁵ is substituted with oneof said substituents. In one embodiment, R¹ is pyrazolyl, pyridyl orpyrazinyl optionally substituted with methyl, trifluoromethyl, methoxyor ethoxy.

Particular example of R¹ when represented by hetAr⁵ include thestructures:

In one embodiment, R¹ is hetAr⁵(CH₂)—, where hetAr⁵ is a 5-6 memberedheteroaryl ring having 1-3 ring heteroatoms independently selected fromN, O or S, wherein the ring is optionally substituted with one or moresubstituents independently selected from halogen, (1-6C)alkyl,(1-6C)alkoxy and CF₃. Examples include pyrrolyl, pyrazolyl, imidazolyl,furanyl, isoxazolyl, oxazolyl, thiophenyl, thiazolyl, thiadiazolyl,triazolyl, thiadiazolyl, pyridyl, pyrimidyl and pyrazinyl rings, whereinthe ring is optionally substituted with one or more substituentsindependently selected from halogen, (1-6C)alkyl, (1-6C)alkoxy and CF₃.

In one embodiment, R¹ is hetAr⁵(CH₂)—, where hetAr⁵ is imidazolyl,thiadiazolyl or triazolyl optionally substituted with one or moresubstituents independently selected from halogen, (1-6C)alkyl,(1-6C)alkoxy and CF₃. In one embodiment, hetAr⁵ is substituted with oneor more substituents independently selected from methyl, methoxy,ethoxy, and trifluoromethyl. In one embodiment, hetAr⁵ is substitutedwith one of said substituents.

Particular example of R¹ when represented by hetAr⁵(CH₂)— include thestructures:

In one embodiment, R¹ is Ar⁵(CH₂)₀₋₁.

In one embodiment, R¹ is Ar⁵, where Ar⁵ phenyl optionally substitutedwith one or more substituents independently selected from halogen,(1-6C)alkyl, (1-6C)alkoxy, CF₃O—, (1-4C)alkoxycarbonyl andaminocarbonyl. In one embodiment, Ar⁵ is phenyl optionally substitutedwith one or more substituents independently selected from F, Cl, methyl,methoxy, trifluoromethoxy and CH₃C(═O)O—.

Examples of R¹ when represented by Ar⁵ include phenyl, 2-methoxyphenyl,2-fluorophenyl, 2-methylphenyl, 2-chlorophenyl,2-trifluoromethoxyphenyl, 2-(methoxycarbonyl) phenyl, 4-fluorophenyl,and 2,6-difluorophenyl.

In one embodiment, R¹ is selected from (1-3C alkoxy)(1-6C)alkyl,difluoro(1-6C)alkyl and trifluoro(1-6C)alkyl.

In one embodiment, R² is H.

In one embodiment, R² is F.

In one embodiment, R² is OH.

In one embodiment, the Y group of Formula I linking the pyrrolidinylring and the B group is a bond.

In one embodiment, the Y group of Formula I linking the pyrrolidinylring and the B group is —O—.

In one embodiment, the Y group of Formula I linking the pyrrolidinylring and the B group is —OCH₂—, where the oxygen of the Y group iscoupled to the pyrrolidinyl ring.

In one embodiment, B is represented by Ring B, where Ring B is Ar¹ andAr¹ is phenyl optionally substituted with one or more substituentsindependently selected from halogen, CF₃, CF₃O—, (1-4C)alkoxy,hydroxy(1-4C)alkyl, (1-6C)alkyl, and CN. Examples include phenyl,fluorophenyl, difluorophenyl, trifluorophenyl, chlorophenyl,trifluoromethylphenyl, methoxyphenyl, cyanophenyl, chlorofluorophenyl,cyanoflurophenyl, and chlorocyanophenyl.

Particular examples of Ring B when represented by Ar¹ include phenyl,2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl,3,4,5-trifluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,3-trifluoromethylphenyl 3-methoxyphenyl, 3-chloro-4-fluorophenyl,4-chloro-3-fluorophenyl, 3-chloro-5-fluorophenyl,3-cyano-5-fluorophenyl, 2-cyanophenyl, 4-cyanophenyl and3-cyano-4-fluorophenyl.

In one embodiment, B is represented by Ring B, where Ring B is Ar¹,wherein Ar¹ is phenyl optionally substituted with one or moresubstituents independently selected from halogen, CF₃, CF₃O—,(1-4C)alkoxy, hydroxy(1-4C)alkyl and (1-6C)alkyl. Examples includephenyl, fluorophenyl, difluorophenyl, trifluorophenyl, chlorophenyl,trifluoromethylphenyl, and methoxyphenyl. Particular examples of Ring Bwhen represented by Ar¹ include phenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl,2,4-difluorophenyl, 2,5-difluorophenyl, 3,4,5-trifluorophenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-trifluoromethylphenyland 3-methoxyphenyl.

In one embodiment, B is represented by Ring B, where Ring B is Ar¹,wherein Ar¹ is phenyl optionally substituted with one or more halogens.

In one embodiment, B is represented by Ring B, where Ring B is Ar¹ asdefined for Formula I and Y is a bond.

In one embodiment, B is represented by Ring B, where Ring B is Ar¹ asdefined for Formula I and Y is —O—. Particular examples include —Y—Bgroups having the structures:

In one embodiment, B is represented by Ring B, where Ring B is Ar¹ asdefined for Formula I and Y is —OCH₂—. A particular example includes a—Y—B group having the structure:

In one embodiment, B is represented by Ring B, where Ring B is hetAr¹,and hetAr¹ is a 5-6 membered heteroaryl having 1-3 ring heteroatomsindependently selected from N, S and O, and is optionally substitutedwith 1-2 groups independently selected from (1-6C)alkyl, halogen, OH,CF₃, NH₂ and hydroxy(1-2C)alkyl. In one embodiment, Ring B is hetAr¹,wherein hetAr¹ is a 5-6 membered heteroaryl having 1-2 ring heteroatomsindependently selected from N, S and O, and optionally substituted with1-2 groups independently selected from (1-6C)alkyl, halogen, OH, CF₃,NH₂ and hydroxy(1-2C)alkyl. Examples of Ring B include pyridyl,thiophenyl, thiazolyl, oxazolyl, and isoxazolyl rings optionallysubstituted with 1-2 groups independently selected from (1-6C)alkyl,halogen, OH, CF₃, NH₂ and hydroxy(1-2C)alkyl. In one embodiment ring Bis a pyridyl, thiophenyl, thiazolyl, oxazolyl, or isoxazolyl ringoptionally substituted with 1-2 groups independently selected fromhalogen and (1-6C)alkyl.

Examples of Ring B when represented by hetAr¹ include pyrid-4-yl,pyrid-3-yl, pyrid-2-yl, 5-fluoropyrid-3-yl, thien-2-yl, thiazol-2-yl,2,4-dimethylthiazol-5-yl, oxazol-5-yl, isoxazol-5-yl, thien-2-yl,5-chloropyrid-3-yl, 5-fluoropyrid-2-yl, 3-fluoropyrid-4-yl,1-methylpyrazol-4-yl having the structures:

In certain embodiments, examples of Ring B when represented by hetAr¹include pyrid-4-yl, pyrid-3-yl, pyrid-2-yl, 5-fluoropyrid-3-yl,thien-2-yl, thiazol-2-yl, 2,4-dimethylthiazol-5-yl, oxazol-5-yl andisoxazol-5-yl having the structures:

In one embodiment ring B is a pyridyl ring optionally substituted with1-2 groups independently selected from (1-6C)alkyl and halogen.

In one embodiment, B is represented by Ring B, where Ring B is hetAr¹ asdefined for Formula I and Y is a bond.

In one embodiment, B is represented by Ring B, where Ring B is hetAr¹ asdefined for Formula I and Y is —O—. A particular example of a —Y—B groupis the structure:

In one embodiment, B is represented by Ring B, where Ring B is hetAr¹ asdefined for Formula I and Y is —OCH₂—. A particular example of a —Y—Bgroup is the structure:

In one embodiment, B is (1-6C)alkyl. Examples include methyl, and ethyl,isopropyl.

In one embodiment, B is (1-6C)alkoxy. An example is isopropoxy.

Reference will now be made to Ring C.

In one embodiment, Ring C is formula C-1:

where R³, R⁴ and R⁵ are as defined for Formula I.

In one embodiment, R³ is H.

In one embodiment, R³ is (1-6C)alkyl. Examples of R³ include methyl orethyl.

In one embodiment, R³ is hydroxy(1-6C)alkyl. An example of R³ is2-hydroxyethyl.

In one embodiment, R³ is Ar², where Ar² is phenyl optionally substitutedwith one or more groups independently selected from halogen, (1-6C)alkyland hydroxymethyl. Examples include phenyl, fluorophenyl, methylphenyland hydroxymethylphenyl.

Examples of R³ when represented by Ar² include phenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl,4-methylphenyl, 3-(hydroxymethyl)phenyl, 3-chlorophenyl,3-chloro-4-fluorophenyl and 3-chloro-2-fluorophenyl. Particular examplesof R³ when represented by Ar² include phenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl,4-methylphenyl and 3-(hydroxymethyl)phenyl.

In one embodiment, R³ is hetCyc¹, where hetCyc¹ is a 5-6-memberedsaturated or partially unsaturated heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O. In one embodiment, R³is a pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, piperidinyl,piperazinyl, tetrahydropyranyl, or morpholinyl ring. An example of R³ istetrahydro-2H-pyran-4-yl.

In one embodiment, R³ is (3-7C)cycloalkyl. In one embodiment R³ iscyclohexyl.

In one embodiment, R³ is hetAr², where hetAr² is 5-6 membered heteroarylring having 1-3 ring heteroatoms independently selected from N, O and Sand optionally substituted with one or more substituents independentlyselected from (1-6C)alkyl and halogen. In one embodiment, R³ is athienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl,pyrimidyl, pyrazinyl, or pyridazinyl optionally substituted with one ormore substituents independently selected from (1-6C)alkyl and halogen.In one embodiment, R³ is pyrazolyl, pyridyl or pyridazinyl optionallysubstituted with one or more groups independently selected from(1-6C)alkyl and halogen. In one embodiment, R³ is pyrazolyl, pyridyl orpyridazinyl optionally substituted with (1-6C)alkyl or halogen. Examplesof R³ when represented by hetAr² include 1-methyl-1H-pyrazol-4-yl,pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyridazinyl and 3-chloropyrid-5-yl.

In one embodiment, R³ is hetAr², where hetAr² is a 5-6 memberedheteroaryl ring having 1-3 ring heteroatoms independently selected fromN, O and S and optionally substituted with (1-6C)alkyl. In oneembodiment, R³ is a thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl,oxadiazolyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl optionallysubstituted with (1-6C)alkyl. In one embodiment, R³ is pyrazolyl,pyridyl or pyridazinyl optionally substituted with (1-6C)alkyl. Examplesof R³ include 1-methyl-1H-pyrazol-4-yl, pyrid-2-yl, pyrid-3-yl,pyrid-4-yl, and pyridazinyl.

In one embodiment, R³ is selected from H, Ar², hetAr² and (1-6C)alkyl.

In one embodiment, R³ is selected from H, Ar² and (1-6C)alkyl.

In one embodiment, R³ is selected from Ar² and (1-6C)alkyl.

In one embodiment, R³ is selected from Ar², hetAr² and (1-6C)alkyl.

In one embodiment, R⁴ is H.

In one embodiment, R⁴ is OH.

In one embodiment, R⁴ is (1-6C)alkyl. Examples of R⁴ include methyl,ethyl, isopropyl and tert-butyl.

In one embodiment, R⁴ is monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl or pentafluoro(2-6C)alkyl.Examples of R⁴ include fluoromethyl, 2-fluoroethyl, difluoromethyl and2,2-difluoroethyl, trifluoromethyl, 2,2,2-trifluoroethyl,3,3,3-trifluoropropyl, 2,2,3,3-tetrafluoropropyl and2,2,3,3,3-pentafluoropropyl

In one embodiment, R⁴ is trifluoro(1-6C)alkyl. An example of R⁴ includesCF₃.

In one embodiment, R⁴ is cyano(1-6C)alkyl. An example of R⁴ includescyanomethyl and 2-cyanopropan-2-yl.

In one embodiment, R⁴ is hydroxy(1-6C)alkyl. Examples of R⁴ includehydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyland 1-hydroxy-2-methylpropan-2-yl.

In one embodiment, R⁴ is dihydroxy(2-6C)alkyl. An example of R⁴ includes2,3-dihydroxypropyl.

In one embodiment, R⁴ is (1-3C alkoxy)(1-6C)alkyl. Examples of R⁴include methoxymethyl, 2-methoxyethyl and 3-methoxypropyl.

In one embodiment, R⁴ is amino(1-6C)alkyl. Examples of R⁴ includeaminomethyl, 2-aminoethyl and 3-aminopropyl.

In one embodiment, R⁴ is aminocarbonyl(1-6C)alkyl. Examples of R⁴include aminocarbonylmethyl and 2-(aminocarbonyl)ethyl.

In one embodiment, R⁴ is (1-3C)alkylsulfonamido(1-6C)alkyl. Examplesinclude CH₃SO₂NHCH₂— and CH₃SO₂NHCH₂CH₂—.

In one embodiment, R⁴ is hydroxycarbonyl(1-6C)alkyl. Examples includeHOC(═O)CH₂— and HOC(═O)CH₂CH₂—.

In one embodiment, R⁴ is hetAr³(1-6C)alkyl, where hetAr³ is a 5-memberedheteroaryl ring having 1-3 ring atoms independently selected from N, Sand O and optionally substituted with (1-6C)alkyl. In one embodiment,hetAr³ is a thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl oroxadiazolyl ring optionally substituted with (1-6C)alkyl. Examples of R⁴when represented by hetAr³(1-6C)alkyl include(1-methyl-1H-1,2,4-triazol-3-yl)methyl and(5-methyl-1,3,4-oxadiazol-2-yl)methyl.

In one embodiment, R⁴ is Ar³(1-6C)alkyl, where phenyl optionallysubstituted with (1-4C)alkoxy or hydroxy(1-4C)alkyl. In one embodiment,Ar³ is phenyl or 4-methoxyphenyl. Examples of R⁴ when represented byAr³(1-6C) alkyl include benzyl and 4-methoxybenzyl.

In one embodiment, R⁴ is (1-6C)alkoxy. Examples include methoxy andethoxy.

In one embodiment, R⁴ is monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxytrifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy orpentafluoro(2-6C)alkoxy. Examples of R⁴ include fluoromethoxy,2-fluoroethoxy, 2,2-difluoromethoxy, trifluoromethoxy,2,2,2-trifluoroethoxy and 2,2-difluoroethoxy. In one embodiment, R⁴ is2-fluoroethoxy.

In one embodiment, R⁴ is cyano(1-6C)alkoxy. An example of R⁴ includescyanomethoxy and 2-cyanoethoxy.

In one embodiment, R⁴ is hydroxy(1-6C)alkoxy. Examples of R⁴ include2-hydroxy-2-methylpropoxy, 2-hydroxyethoxy, 2-hydroxypropoxy,2-hydroxy-2-methylpropoxy and 2-hydroxybutoxy.

In one embodiment, R⁴ is dihydroxy(2-6C)alkoxy. Examples of R⁴ include2,3-dihydroxypropoxy and 3-hydroxy-2-(hydroxymethyl)propoxy.

In one embodiment, R⁴ is amino(2-6C)alkoxy. An example is H₂NCH₂CH₂O—.

In one embodiment, R⁴ is aminocarbonyl(1-6C)alkoxy. Examples includeH₂NC(═O)CH₂O— and H₂NC(═O)CH₂CH₂O—.

In one embodiment, R⁴ is hetCyc²(1-6C)alkoxy, where hetCyc² is a 4-6membered heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N and O, wherein hetCyc² is optionally substituted with1-2 groups independently selected from (1-6C)alkyl, (1-4Calkoxy)carbonyl, and (1-6C)acyl. Examples of hetCyc² include oxetaynyl,tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, and 1,3-dioxolanyl ringsoptionally substituted with 1-2 groups independently selected from(1-6C)alkyl, (1-4C alkoxy)carbonyl and (1-6C)acyl. Examples of R⁴ whenrepresented by hetCyc²(1-6C)alkoxy include oxetan-2-ylmethoxy,2-(oxetan-2-yl)propoxy, (2,2-dimethyl-1,3-dioxolan-4-yl)methoxy,(1,3-dioxolan-4-yl)methoxy, 2-morpholinoethoxy, piperazinylethyoxy andpiperidinylethoxy groups optionally substituted with 1-2 groupsindependently selected from (1-6C)alkyl, (1-4C alkoxy)carbonyl and(1-6C)acyl. Particular examples include the structures:

In one embodiment, R⁴ is hetCyc²(1-6C)alkoxy, where hetCyc² is a 4-6membered heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N and O, wherein hetCyc² is optionally substituted with1-2 groups independently selected from (1-6C)alky. Examples ofheterocyclic rings include oxetaynyl, tetrahydrofuranyl,tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, and 1,3-dioxolanyl rings optionally substituted with 1-2groups independently selected from (1-6C)alkyl. Examples of R⁴ whenrepresented by hetCyc²(1-6C)alkoxy include oxetan-2-ylmethoxy,2-(oxetan-2-yl)propoxy, (2,2-dimethyl-1,3-dioxolan-4-yl)methoxy,(1,3-dioxolan-4-yl)methoxy and 2-morpholinoethoxy, piperazinylethyoxyrings optionally substituted with (1-6C)alkyl, such as:

In one embodiment, R⁴ when represented by hetCyc²(1-6C)alkoxy isselected from oxetan-2-ylmethoxy, 2-(oxetan-2-yl)propoxy,(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy, (1,3-dioxolan-4-yl)methoxy and2-morpholinoethoxy.

In one embodiment, R⁴ is hetAr³(1-6C)alkoxy, where hetAr³ is a5-membered heteroaryl ring having 1-3 ring atoms independently selectedfrom N, S and O and optionally substituted with (1-6C)alkyl. In oneembodiment, hetAr³ is a thienyl, furyl, imidazolyl, pyrazolyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolylor oxadiazolyl ring optionally substituted with (1-6C)alkyl. In oneembodiment, hetAr³ is triazolyl or oxadiazolyl ring optionallysubstituted with a (1-6C)alkyl group such as a methyl group. Examples ofR⁴ when represented by hetAr³(1-6C)alkoxy include(1-methyl-1H-1,2,4-triazol-3-yl)methoxy and(5-methyl-1,3,4-oxadiazol-2-yl)methoxy, which can be represented by thestructures:

In one embodiment, R⁴ is Ar³(1-6C)alkoxy, where Ar³ is phenyl optionallysubstituted with (1-4C)alkoxy. Examples include phenylmethoxy and(4-methoxyphenyl)methoxy having the structures:

In one embodiment, R⁴ is (1-4C alkoxy)(1-6C)alkoxy. Examples include(2-methoxy)ethoxy having the structure:

In one embodiment, R⁴ is (1-3Calkylsulfonyl)(1-6C)alkoxy. Examplesinclude (2-methyl sulfonyl)ethoxy having the structure:

In one embodiment, R⁴ is (3-6C)cycloalkyl optionally substituted with F,OH, (1-6C alkyl), (1-6C)alkoxy, or (1-3C alkoxy)(1-6C)alkyl. Examplesinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2-hydroxycyclobutyl. In one embodiment, R⁴ is cyclopropyl or2-hydroxycyclobutyl. In one embodiment, R⁴ is cyclopropyl.

In one embodiment, R⁴ is (3-6C)cycloalkyl. Examples include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 2-hydroxycyclobutyl. In oneembodiment, R⁴ is cyclopropyl.

In one embodiment, R⁴ is hetAr⁴, where hetAr⁴ is a 5-6 memberedheteroaryl ring having 1-3 ring heteroatoms independently selected fromN, S and O and optionally substituted with 1-2 substituentsindependently selected from (1-6C)alkyl, halogen, CN,hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH₂-(3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino, (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl, andmethoxybenzyl; or a 9-10 membered bicyclic heteroaryl having 1-3 ringnitrogen atoms.

Examples include pyridyl, pyrimidinyl pyridazinyl, pyrazolyl,imidazolyl, thienyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiazolyl,oxazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl andimidazo[1,2-a]pyridinyl rings optionally substituted with 1-2substituents independently selected from (1-6C)alkyl,hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH₂-(3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino, (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl, andmethoxybenzyl.

In one embodiment, R⁴ is hetAr⁴, where hetAr⁴ is a pyridyl, pyrimidinylpyridazinyl, pyrazolyl, imidazolyl, thionyl, 1,2,4-triazolyl,1,2,3-triazolyl, thiazolyl, oxazolyl, 1,3,4-oxadiazolyl,1,2,4-oxadiazolyl or imidazo[1,2-a]pyridinyl ring optionally substitutedwith 1-2 substituents independently selected from fluoro, methyl, ethyl,isopropyl, cyclopropylmethyl, cyclopropyl, trifluoromethyl,2,2,2-trifluoroethyl, methoxy, H₂N—, (CH₃)₂N—, 2-hydroxyethyl,2-methoxyethyl, 1-(2,2,2-trifluoroethoxy)-2,2,2-trifluoroethyl,cyclopropylcarbonyl, methylsulfonyl and 4-methoxybenzyl.

In one embodiment, examples of R⁴ when represented by hetAr⁴ include thestructures:

In one embodiment, R⁴ is hetAr⁴, where hetAr⁴ is a 5-6 memberedheteroaryl ring having 1-3 ring heteroatoms independently selected fromN, S and O and optionally substituted with 1-2 substituentsindependently selected from (1-6C)alkyl, or a 9-10 membered bicyclicheteroaryl having 1-3 ring nitrogen atoms. In one embodiment, hetAr⁴ isa 5-6 membered heteroaryl ring having 1-2 ring heteroatoms independentlyselected from N and S and optionally substituted with 1-2 substituentsindependently selected from (1-6C)alkyl, or a 9-membered bicyclicheteroaryl having 1-2 ring nitrogen atoms. Examples include pyridyl,pyridazinyl, pyrazolyl, thienyl and imidazo[1,2-a]pyridinyl ringsoptionally substituted with 1-2 substituents independently selected from(1-6C)alkyl.

In one embodiment, examples of R⁴ when represented by hetAr⁴ includepyridn-2-yl, pyridin-3-yl, pyridine-4-yl, 5-methylpyridazin-2-yl,pyridazin-2-yl, 1-methylpyrazol-4-yl, thien-2-yl andimidazo[1,2-a]pyridine-5-yl having the structures:

In one embodiment, R⁴ is Ar⁴, where Ar⁴ is phenyl optionally substitutedwith one or more groups independently selected from (1-6C)alkyl,halogen, CN, CF₃, CF₃O—, (1-6C)alkoxy, (1-6Calkyl)OC(═O)—,aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—,HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—. Examples include phenyloptionally substituted with one or more groups independently selectedfrom methyl, F, Cl, CN, methoxy, CH₃OC(═O)—, aminocarbonyl,methylaminocarbonyl, dimethylaminocarbonyl, methylthio, hydroxymethyl,CH₃SO₂—, HOC(═O)— and CH₃OCH₂CH₂OC(═O)—. In certain embodiments, R⁴ isphenyl optionally substituted with one or two of said substituents.Particular examples include the structures:

In one embodiment, R⁴ is hetCyc²(O)CH₂, where hetCyc² is a 4-6 memberedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O, wherein hetCyc² is optionally substituted with 1-2 groupsindependently selected from (1-6C)alkyl, (1-4C alkoxy)carbonyl, and(1-6C)acyl. Examples of hetCyc² include oxetaynyl, tetrahydrofuranyl,tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, and 1,3-dioxolanyl rings optionally substituted with 1-2groups independently selected from (1-6C)alkyl, (1-4C alkoxy)carbonyland (1-6C)acyl. Examples of R⁴ when represented by hetCyc²(1-6C)alkoxyinclude piperazinylethyoxy and piperidinylethoxy groups optionallysubstituted with 1-2 groups independently selected from (1-6C)alkyl,(1-4C alkoxy)carbonyl and (1-6C)acyl. Particular examples include thestructures:

In one embodiment, R⁴ is (1-4C alkoxycarbonyl)(1-6C)alkoxy. Examplesinclude methoxycarbonyl(1-6C)alkoxy and ethylcarbonyl(1-6C)alkoxy. Aparticular example is ethoxycarbonylmethoxy.

In one embodiment, R⁴ is hydroxycarbonyl(1-6C)alkoxy. A particularexample is hydroxycarbonylmethoxy.

In one embodiment, R⁴ is aminocarbonyl(1-6C)alkoxy. Examples includeH₂NC(═O)(1-6C)alkoxy, (1-6C alkyl)NHC(═O)(1-6C)alkoxy, anddi(1-6Calkyl)NC(═O)(1-6C)alkoxy. A particular example isCH₃CH₂NC(═O)CH₂O—.

In one embodiment, R⁴ is hetCyc²C(═O)(1-6C)alkoxy, where hetCyc² is a4-6 membered heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N and O and optionally substituted with 1-2 groupsindependently selected from (1-6C)alkyl, (1-4C alkoxy)carbonyl, and(1-6C)acyl. Examples of hetCyc² include oxetaynyl, tetrahydrofuranyl,tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, and 1,3-dioxolanyl rings optionally substituted with 1-2groups independently selected from (1-6C)alkyl, (1-4C alkoxy)carbonyland (1-6C)acyl. In one embodiment, hetCyc² is morpholinyl. A particularexample of R⁴ when represented by hetCyc²C(═O)(1-6C)alkoxy is thestructure:

In one embodiment, R⁴ is hydroxy(1-3C alkoxy)(1-6C)alkoxy. A particularexample is 2-hydroxy-3-methoxypropoxy, having the structure:

In one embodiment, R⁴ is hydroxytrifluoro(1-6C)alkoxy. A particularexample is 3,3,3-difluoro-2-hydroxypropoxy having the structure:

In one embodiment, R⁴ is (1-3C)alkylsulfonamido(1-6C)alkoxy. Examplesinclude methanesulfonamido(1-6C)alkoxy. A particular example is2-methanesulfonamidoethoxy having the structure:

In one embodiment, R⁴ is (1-3C)alkylamido(1-6C)alkoxy. A particularexample is 2-(methylamido)ethoxy having the structure:

In one embodiment, R⁴ is di(1-3C alkyl)aminocarboxy. A particularexample is dimethylaminocarboxy having the structure:

In one embodiment, R⁴ is hetCyc²C(═O)O—, where hetCyc² is a 4-6 memberedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O and optionally substituted with 1-2 groups independentlyselected from (1-6C)alkyl, (1-4C alkoxy)carbonyl and (1-6C)acyl.Examples of hetCyc² include oxetaynyl, tetrahydrofuranyl,tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, and 1,3-dioxolanyl rings optionally substituted with 1-2groups independently selected from (1-6C)alkyl, (1-4C alkoxy)carbonyland (1-6C)acyl. In one embodiment, hetCyc² is morpholinyl. A particularexample of R⁴ when represented by hetCyc²C(═O)O— is the structure:

In one embodiment, R⁴ is hydroxydifluoro(1-6C)alkyl. An example includes2,2-difluro-2-hydroxyethyl.

In one embodiment, R⁴ is (1-4C alkylcarboxy)(1-6C)alkyl. Examplesinclude methylcarboxy(1-6C)alkyl. A particular example is2-(methylcarboxy)ethyl.

In one embodiment, R⁴ is (1-6C)alkoxycarbonyl. Examples includemethoxycarbonyl and ethoxycarbonyl.

In one embodiment, R⁴ is hydroxycarbonyl.

In one embodiment, R⁴ is aminocarbonyl, that is, a RR′NCO— radical whereR and R′ are independently hydrogen or (1-6C)alkyl as defined herein.Examples include aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, ethylcarbonyl and isopropylaminocarbonyl.

In one embodiment, R⁴ is (1-3C alkoxy)aminocarbonyl. An example includesmethoxyaminocarbonyl.

In one embodiment, R⁴ is hetCyc³, where is a 4-7 membered heterocyclehaving 1-2 ring heteroatoms independently selected from N and O andoptionally substituted with one or more substituents independentlyselected from F, CN, CF₃, (1-6C)alkyl, hydroxy(1-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, (1-6C)acyl-, (1-6C)alkylsulfonyl,trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl. In one embodiment,hetCyc³ is tetrahydropyranyl, piperidinyl, pyrrolidinyl or azetidinyloptionally substituted with one or more substituents independentlyselected from F, CN, CF₃, (1-6C)alkyl, hydroxy(1-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, (1-6C)acyl-, (1-6C)alkylsulfonyl,trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl. In one embodiment,hetCyc³ is optionally substituted with one or two of said substituents.In one embodiment, hetCyc³ is tetrahydropyranyl, piperidinyl,pyrrolidinyl or azetidinyl optionally substituted with CN, Me,CH₃C(═O)—, MeSO₂—, CF₃SO₂— or (CH₃)₃COC(═O)—. Particular examples of R⁴when represented by hetCyc³ include the structures:

In one embodiment, R⁴ is halogen. In one embodiment, R⁴ is Br.

In one embodiment, R⁴ is CN.

In one embodiment, R⁴ is trifluoromethylsulfonyl.

In one embodiment, R⁴ is N-(1-3C alkyl)pyridinonyl. Examples includeN-(1-3C alkyl) substituted pyridin-2(1H)-on-4-yl and N-(1-3C alkyl)substituted pyridin-2(1H)-on-5-yl groups. Particular examples includethe structures:

In one embodiment, R⁴ is N-(1-3C trifluoroalkyl)pyridinonyl. Examplesinclude N-(1-3C trifluoroalkyl)-substituted pyridin-2(1H)-on-4-yl andN-(1-3C trifluoroalkyl)-substituted pyridin-2(1H)-on-5-yl groups. Aparticular example includes the structure:

In one embodiment, R⁴ is (1-4C alkylsiloxy)(1-6C)alkoxy. Examplesinclude tert-butylsiloxy(1-6C)alkoxy groups. A particular example is2-(tert-butylsiloxy)propoxy.

In one embodiment, R⁴ is isoindoline-1,3-dionyl(1-6C)alkoxy. Aparticular example includes the structure:

In one embodiment, R is N-(1-3C alkyl)oxadiazolonyl, Particular examplesinclude the structures:

In one embodiment, R⁴ is selected from H, (1-6C)alkyl,trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, cyano(1-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, (1-6C)alkoxy, monofluoro (1-6C)alkoxy,cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy,hetCyc²(1-6C)alkoxy, Ar³(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3Calkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [optionally substitutedwith F, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(1-6C)alkyl],hetAr⁴, Ar⁴, (1-4C alkoxycarbonyl)(1-6C)alkoxy,hydroxycarbonyl(1-6C)alkoxy, aminocarbonyl(1-6C)alkoxy,hetCyc²C(═O)(1-6C)alkoxy, hydroxy(1-3C alkoxy)(1-6C)alkoxy,hydroxytrifluoro(1-6C)alkoxy, (1-3C)alkylsulfonamido(1-6C)alkoxy,(1-3C)alkylamido(1-6C)alkoxy, di(1-3C alkyl)aminocarboxy,hetCyc²C(═O)O—, hydroxydifluoro(1-6C)alkyl, (1-4Calkylcarboxy)(1-6C)alkyl, (1-6C)alkoxy-carbonyl, hydroxycarbonyl,aminocarbonyl, (1-3C alkoxy)aminocarbonyl, hetCyc³, halogen, CN,trifluoromethylsulfonyl, N-(1-3C alkyl)pyridinonyl, N-(1-3Ctrifluoroalkyl)pyridinonyl, (1-4C alkylsiloxy)(1-6C)alkoxy,isoindoline-1,3-dionyl(1-6C)alkoxy and N-(1-3C alkyl)oxadiazolonyl.

In one embodiment, R⁴ is selected from H, (1-6C)alkyl,trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, cyano(1-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, (1-6C)alkoxy, monofluoro (1-6C)alkoxy,cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, hetCyc²(1-6C)alkoxy, Ar³(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3Calkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr⁴ and Ar⁴.

In one embodiment, R⁴ is selected from H, (1-6C)alkyl,trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, cyano(1-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, (1-6C)alkoxy, monofluoro(1-6C)alkoxy,cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy,hetCyc²(1-6C) alkoxy, Ar³(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3Calkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr⁴ and Ar⁴.

In one embodiment, R⁴ is selected from H, (1-6C)alkyl,trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4Calkoxy)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr⁴ and Ar⁴.

In one embodiment, R⁴ is selected from (1-6C)alkyl,trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl and(3-6C)cycloalkyl.

In one embodiment, R⁴ is selected from (1-6C)alkoxy, cyano(1-6C)alkoxy,hydroxy(1-6C)alkoxy and (1-4C alkoxy)(1-6C)alkoxy.

In one embodiment, R⁴ is selected from hetAr⁴ and Ar⁴.

In one embodiment, R⁵ is H.

In one embodiment, R⁵ is (1-6C)alkyl. Examples include methyl, ethyl,propyl, isopropyl and butyl.

In one embodiment, R⁵ is monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluro(2-6C)alkyl or pentafluro(2-6C)alkyl.Examples include fluoromethyl, 2-fluoroethyl, difluoromethyl,2,2-difluoroethyl, 1,3-difluoroprop-2-yl, trifluoromethyl,2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 1,1,2,2-tetrafluoropropaneand 2,2,3,3,3-pentafluoropropyl.

In one embodiment, R⁵ is halogen. In one embodiment, R⁵ is F. In oneembodiment, R⁵ is Cl. In one embodiment, R⁵ is Br.

In one embodiment, R⁵ is CN.

In one embodiment, R⁵ is (1-4C)alkoxy. Examples include methoxy andethoxy.

In one embodiment, R⁵ is hydroxy(1-4C)alkyl. Examples includehydroxymethyl and 3-hydroxypropyl.

In one embodiment, R⁵ is (1-4C alkyl)OC(═O)—. Examples includeCH₃CH₂OC(═O)—.

In one embodiment, R⁵ is (1-6C)alkylthio. An example is methylthio(MeS—).

In one embodiment, R⁵ is phenyl optionally substituted with one or moregroups independently selected from halogen, (1-6C)alkyl and(1-6C)alkoxy. In one embodiment, R⁵ is phenyl optionally substitutedwith one or more groups independently selected from F, Cl, methyl,ethyl, methoxy and ethoxy. In one embodiment, R⁵ is phenyl.

In one embodiment, R⁵ is (3-4C)cycloalkyl. In one embodiment, R⁵ iscyclopropyl. In one embodiment, R⁵ is cyclobutyl.

In one embodiment, R⁵ is amino. In one embodiment, R⁵ is NH₂.

In one embodiment, R⁵ is aminocarbonyl. In one embodiment, R⁵ isH₂NC(═O)—.

In one embodiment, R⁵ is trifluoro(1-3C alky)amido. In one embodiment,R⁵ is CF₃C(═O)NH—.

In one embodiment, R⁵ is selected from H, halogen, CN, (1-6C)alkyl,(1-4C)alkoxy, hydroxy(1-4C)alkyl, or phenyl optionally substituted withone or more groups independently selected from halogen, (1-6C)alkyl and(1-6C)alkoxy.

In one embodiment, R⁵ is selected from H, halogen, or (1-6C)alkyl.

In one embodiment, R⁵ is selected from H, methyl, Cl or Br.

In one embodiment of Formula I, R⁴ is H, OH, (1-6C)alkyl,monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl,tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl, cyano(1-6C)alkyl,hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl,amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl,(1-3C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl,hydroxyl-carbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar³(1-6C)alkyl,(1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxytrifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxycyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy,amino(2-6C)alkoxy, amino-carbonyl(1-6C)alkoxy,hydroxycarbonyl(1-6C)alkoxy, hetCyc²(1-6C)alkoxy, hetAr³(1-6C)alkoxy,Ar³(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3Calkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [optionally substitutedwith F, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(1-6C)alkyl],hetAr⁴, Ar⁴, (1-4C alkoxycarbonyl)(1-6C)alkoxy,hydroxycarbonyl(1-6C)alkoxy, aminocarbonyl(1-6C)alkoxy,hetCyc²C(═O)(1-6C)alkoxy, hydroxy(1-3C alkoxy)(1-6C)alkoxy,hydroxytrifluoro(1-6C)alkoxy, (1-3C)alkylsulfonamido(1-6C)alkoxy,(1-3C)alkylamido(1-6C)alkoxy, di(1-3C alkyl) aminocarboxy,hetCyc²C(═O)O—, hydroxydifluoro(1-6C)alkyl, (1-4Calkylcarboxy)(1-6C)alkyl, (1-6C)alkoxycarbonyl, hydroxycarbonyl,aminocarbonyl, (1-3C alkoxy)amino-carbonyl, hetCyc³, halogen, CN,trifluoromethylsulfonyl, N-(1-3C alkyl)pyridinonyl, N-(1-3Ctrifluoroalkyl) pyridinonyl, (1-4C alkylsiloxy)(1-6C)alkoxy,isoindoline-1,3-dionyl(1-6C)alkoxy or N-(1-3C alkyl)oxadiazolonyl; andR⁵ is H, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl,halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl,(1-4C alkyl)OC(═O)—, (1-6C)alkylthio, phenyl [optionally substitutedwith one or more groups independently selected from halogen, (1-6C)alkyland (1-6C)alkoxy], (3-4C)cycloalkyl, amino, aminocarbonyl, ortrifluoro(1-3C alky)amido.

In one embodiment of Formula I, R⁴ is H, OH, (1-6C)alkyl,monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl,tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl, cyano(1-6C)alkyl,hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl,amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl,(1-3C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl,hydroxyl-carbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar³(1-6C) alkyl,(1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy,trifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxy,cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy,amino(2-6C)alkoxy, aminocarbonyl(1-6C)alkoxy,hydroxycarbonyl(1-6C)alkoxy, hetCyc²(1-6C)alkoxy, hetAr³(1-6C)alkoxy,Ar³(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3Calkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr⁴, or Ar⁴; and R⁵ isH, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl,halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl,(1-4C alkyl)OC(═O)—, (1-6C)alkylthio, or phenyl optionally substitutedwith one or more groups independently selected from halogen, (1-6C)alkyland (1-6C)alkoxy.

In one embodiment of Formula I, R⁴ is selected from H, (1-6C)alkyl,trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4Calkoxy)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr⁴ and Ar⁴, and R⁵ isselected from H, halogen, CN, (1-6C)alkyl, (1-4C)alkoxy,hydroxy(1-4C)alkyl, (1-6C)alkylthio, or phenyl optionally substitutedwith one or more groups independently selected from halogen, (1-6C)alkyland (1-6C)alkoxy.

In one embodiment, R⁴ and R⁵ together with the atoms to which they areattached form a 5-6 membered saturated, partially unsaturated orunsaturated carbocyclic ring optionally substituted with one or moresubstituents independently selected from (1-6C)alkyl; or R⁴ and R⁵together with the atoms to which they are attached form a 5-6 memberedsaturated, partially unsaturated or unsaturated heterocyclic ring havinga ring heteroatom selected from N, O or S, wherein said heterocyclicring is optionally substituted with one or two substituentsindependently selected from (1-6C alkyl)C(═O)O—, (1-6)acyl, (1-6C)alkyland oxo, and said sulfur ring atom is optionally oxidized to S(═O) orSO₂.

In one embodiment, R⁴ and R⁵ together with the atoms to which they areattached form a 5-6 membered saturated, partially unsaturated orunsaturated carbocyclic ring optionally substituted with one or moresubstituents independently selected from (1-6C)alkyl. Examples of Ring Cwhen R⁴ and R⁵ together with the atoms to which they are attached form a5-6 membered saturated or unsaturated carbocyclic ring include thestructures:

where R³ is as defined for Formula I.

In one embodiment, R⁴ and R⁵ together with the atoms to which they areattached form a 5-6 membered saturated carbocyclic ring optionallysubstituted with one or more substituents independently selected from(1-6C)alkyl, or R⁴ and R⁵ together with the atoms to which they areattached form a 5-6 membered saturated heterocyclic ring having a ringheteroatom selected from N, O or S, wherein said ring nitrogen atom isoptionally substituted with (1-6C alkyl)C(═O)O— or (1-6)acyl, and saidsulfur ring atom is optionally oxidized to S(═O) or SO₂.

In one embodiment, R⁴ and R⁵ together with the atoms to which they areattached form a 5-6 membered saturated carbocyclic ring optionallysubstituted with one or more substituents independently selected from(1-6C)alkyl. Examples of Ring C when R⁴ and R⁵ together with the atomsto which they are attached form a 5-6 membered saturated carbocyclicring include the structures:

where R³ is as defined for Formula I.

In one embodiment, R⁴ and R⁵ together with the atoms to which they areattached form a 5-6 membered saturated, partially unsaturated orunsaturated heterocyclic ring having a ring heteroatom selected from N,O or S, wherein said ring N atom is optionally substituted with (1-6Calkyl)C(═O)O—, (1-6C alkyl)C(═O)—, (1-6C)alkyl or oxo, and said S ringatom is optionally oxidized to S(═O) or SO₂. Examples of Ring C when R⁴and R⁵ together with the atoms to which they are attached form a 5-6membered saturated heterocyclic ring include the structures:

where R³ is as defined for Formula I.

In one embodiment, R⁴ and R⁵ together with the atoms to which they areattached form a 5-6 membered saturated heterocyclic ring having a ringheteroatom selected from N, O or S, wherein said ring N atom isoptionally substituted with (1-6C alkyl)C(═O)O— or (1-6C alkyl)C(═O)—,and said S ring atom is optionally oxidized to S(═O) or SO₂. Examples ofRing C when R⁴ and R⁵ together with the atoms to which they are attachedform a 5-6 membered saturated heterocyclic ring include the structures:

where R³ is as defined for Formula I.

In one embodiment, Ring C is formula C-2

where R^(3a), R^(4a) and R^(5a) are as defined for Formula I.

In one embodiment, R^(3a) is hydrogen.

In one embodiment, R^(3a) is halogen.

In one embodiment, R^(3a) is (1-6C)alkyl. In one embodiment, R^(3a) ismethyl.

In one embodiment, R^(3a) is trifluoro(1-6C)alkyl. In one embodiment,R^(3a) is CF₃.

In one embodiment, R^(3a) is (3-6C)cycloalkyl. In one embodiment, R^(3a)is cyclopropyl.

In one embodiment, R^(3a) is phenyl optionally substituted with one ormore substituents independently selected from halogen, (1-6C)alkyl andhydroxymethyl. Examples include phenyl, fluorophenyl, methylphenyl andhydroxymethylphenyl, for example include phenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl,4-methylphenyl, 3-(hydroxymethyl)phenyl, 3-chlorophenyl,3-chloro-4-fluorophenyl and 3-chloro-2-fluorophenyl. In one embedment,R^(3a) is phenyl.

In one embodiment, R^(3a) is a 5-6 membered heteroaryl ring having 1-3ring heteroatoms independently selected from N, O and S and optionallysubstituted with one or more groups independently selected from(1-6C)alkyl and halogen. In one embodiment, R^(3a) is a thienyl, furyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidyl, pyrazinyl, orpyridazinyl ring optionally substituted with (1-6C)alkyl or halogen. Inone embodiment, R^(3a) is pyrazolyl, pyridyl or pyridazinyl optionallysubstituted with one or more groups independently selected from(1-6C)alkyl and halogen. In one embodiment, R^(3a) is pyrazolyl, pyridylor pyridazinyl optionally substituted with (1-6C)alkyl or halogen.

In one embodiment, R^(4a) is hydrogen.

In one embodiment, R^(4a) is (1-6C)alkyl. In one embodiment, R^(4a) ismethyl, ethyl or isopropyl.

In one embodiment, R^(4a) is trifluoro(1-6C)alkyl. In one embodiment,R^(4a) is 2,2,2-trifluoroethyl.

In one embodiment, R^(4a) is phenyl optionally substituted with one ormore groups independently selected from (1-6C)alkyl, halogen, CN, CF₃,CF₃O—, (1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio,hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3Calkyl)OC(═O)—. Examples include phenyl optionally substituted with oneor more groups independently selected from methyl, F, Cl, CN, methoxy,CH₃OC(═O)—, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl,methylthio, hydroxymethyl, CH₃SO₂—, HOC(═O)— and CH₃OCH₂CH₂OC(═O)—. Incertain embodiments, R^(4a) is phenyl optionally substituted with one ortwo of said substituents. In one embodiment, R^(4a) is phenyl.

In one embodiment, R^(4a) is a 5-6 membered heteroaryl ring having 1-3ring heteroatoms independently selected from N, S and O and optionallysubstituted with 1-2 substituents independently selected from(1-6C)alkyl, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl,(3-6C cycloalkyl)CH₂-(3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino, (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl, andmethoxybenzyl. Examples include pyridyl, pyrimidinyl pyridazinyl,pyrazolyl, imidazolyl, thionyl, 1,2,4-triazolyl, 1,2,3-triazolyl,thiazolyl, oxazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl andimidazo[1,2-a]pyridinyl rings optionally substituted with 1-2substituents independently selected from (1-6C)alkyl,hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH₂-(3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino, (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl, andmethoxybenzyl. In one embodiment, R^(4a) is pyrazinyl.

In one embodiment, R^(5a) is as defined for Formula I.

In one embodiment, R^(5a) is selected from hydrogen, halogen,(1-6C)alkyl and phenyl.

In one embodiment, R^(5a) is hydrogen.

In one embodiment, R^(5a) is halogen.

In one embodiment, R^(5a) is (1-6C)alkyl. In one embodiment, R^(5a) ismethyl.

In one embodiment, R^(5a) is phenyl.

In one embodiment, Ring C is formula C-2, in which R^(3a) is(1-6C)alkyl, trifluoro(1-6C)alkyl or phenyl; R^(4a) is (1-6C)alkyl,trifluoro(1-6C)alkyl, phenyl or pyrazinyl; and R^(5a) is hydrogen,(1-6C)alkyl or phenyl.

In one embodiment, Ring C is formula C-3

where R^(3b) is as defined for Formula I.

In one embodiment, R^(3b) is hydrogen.

In one embodiment, R^(3b) is (1-6C)alkyl. In one embodiment, R^(3b) ismethyl.

In one embodiment, R^(3b) is trifluoro(1-6C)alkyl. In one embodiment,R^(3b) is CF₃.

In one embodiment, R^(3b) is (3-6C)cycloalkyl. In one embodiment, R^(3b)is cyclopropyl.

In one embodiment, R^(3b) is phenyl optionally substituted with one ormore substituents independently selected from halogen, (1-6C)alkyl andhydroxymethyl. In one embedment, R^(3b) is phenyl.

In one embodiment, R^(3b) is a 5-6 membered heteroaryl ring having 1-3ring heteroatoms independently selected from N, O and S and optionallysubstituted with one or more groups independently selected from(1-6C)alkyl and halogen. In one embodiment, R^(3b) is a thienyl, furyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidyl, pyrazinyl, orpyridazinyl optionally substituted with (1-6C)alkyl or halogen. In oneembodiment, R^(3b) is pyrazolyl, pyridyl or pyridazinyl optionallysubstituted with one or more groups independently selected from(1-6C)alkyl and halogen. In one embodiment, R^(3b) is pyrazolyl, pyridylor pyridazinyl optionally substituted with (1-6C)alkyl or halogen.

In one embodiment, Ring C is formula C-3 where R^(3b) is hydrogen orphenyl.

In another embodiment of the present invention there is provided acompound according to Formula I, which is designated as Formula I-a,wherein:

X is O;

B is Ar¹;

Y is a bond;

Ring C is

R⁴ is H, OH, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl,cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl,(1-3C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl,hydroxycarbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar³(1-6C)alkyl,(1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy,trifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxy,cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy,amino(2-6C)alkoxy, aminocarbonyl(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy, hetCyc²(1-6C)alkoxy, hetAr³(1-6C)alkoxy, Ar³(1-6C)alkoxy,(1-4C alkoxy)(1-6C)alkoxy, (1-3C alkylsulfonyl)(1-6C)alkoxy,(3-6C)cycloalkyl, hetAr⁴, or Ar⁴;

R⁵ is H, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl,halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl,(1-4C alkyl)OC(═O)—, or phenyl optionally substituted with one or moregroups independently selected from halogen, (1-6C)alkyl and(1-6C)alkoxy; and R^(a), R^(b), R^(c), R^(d), R¹, R², Ar¹, R³, hetCyc²,hetAr³, Ar³, hetAr⁴ and Ar⁴ are as defined for Formula I.

In one embodiment of Formula I-a, R^(a), R^(b), R^(c) and R^(d) arehydrogen; R² is hydrogen; and R¹, Ar¹, R³, hetCyc², hetAr³, Ar³, hetAr⁴,and Ar⁴ are as defined for Formula I.

In one embodiment of Formula I-a, R^(a), R^(b), R^(c) and R^(d) arehydrogen; R² is hydrogen; R¹ is (1-3C alkoxy)(1-6C)alkyl,difluoro(1-6C)alkyl, or trifluoro(1-6C)alkyl; and Ar¹, R³, hetCyc²,hetAr³, Ar³, hetAr⁴ and Ar⁴ are as defined for Formula I.

In one embodiment of Formula I-a, R^(a), R^(b), R^(c) and R^(d) arehydrogen; R² is hydrogen; R¹ is (1-3C alkoxy)(1-6C)alkyl,difluoro(1-6C)alkyl, or trifluoro(1-6C)alkyl; R³ is Ar², hetAr² or(1-6C)alkyl; and Ar¹, Ar², hetAr², hetCyc², hetAr³, Ar³, hetAr⁴, and Ar⁴are as defined for Formula I.

In one embodiment of Formula I-a, R^(a), R^(b), R^(c) and R^(d) arehydrogen; R² is hydrogen; R¹ is (1-3C alkoxy)(1-6C)alkyl,difluoro(1-6C)alkyl, or trifluoro(1-6C)alkyl; R³ is Ar², hetAr² or(1-6C)alkyl; R⁴ is H, (1-6C)alkyl, trifluoro(1-6C)alkyl,cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy,cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy,(3-6C)cycloalkyl, hetAr⁴ or Ar⁴; and Ar¹, Ar², hetAr², hetCyc², hetAr³,Ar³, hetAr⁴, and Ar⁴ are as defined for Formula I.

In one embodiment of Formula I-a, R^(a), R^(b), R^(c) and R^(d) arehydrogen; R² is hydrogen; R¹ is (1-3C alkoxy)(1-6C)alkyl,difluoro(1-6C)alkyl, or trifluoro(1-6C)alkyl; R³ is Ar², hetAr² or(1-6C)alkyl; R⁴ is hetAr⁴ or Ar⁴; and Ar¹, Ar², hetAr², hetCyc², hetAr³,Ar³, hetAr⁴, and Ar⁴ are as defined for Formula I.

In one embodiment of Formula I-a, R^(a), R^(b), R^(c) and R^(d) arehydrogen; R² is hydrogen; R¹ is (1-3C alkoxy)(1-6C)alkyl,difluoro(1-6C)alkyl, or trifluoro(1-6C)alkyl; R³ is Ar², hetAr² or(1-6C)alkyl; R⁴ is H, (1-6C)alkyl, trifluoro(1-6C)alkyl,cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy,cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy,(3-6C)cycloalkyl, hetAr⁴ or Ar⁴; R⁵ is H, halogen, CN, (1-6C)alkyl,(1-4C)alkoxy, hydroxy(1-4C)alkyl, or phenyl optionally substituted withone or more groups independently selected from halogen, (1-6C)alkyl and(1-6C)alkoxy; and Ar¹, Ar², hetAr² hetCyc², hetAr³, Ar³, hetAr⁴, and Ar⁴are as defined for Formula I.

In one embodiment of Formula I-a, R^(a), R^(b), R^(c) and R^(d) arehydrogen; R² is hydrogen; R¹ is (1-3C alkoxy)(1-6C)alkyl,difluoro(1-6C)alkyl, or trifluoro(1-6C)alkyl; R³ is Ar², hetAr² or(1-6C)alkyl; R⁴ is H, (1-6C)alkyl, trifluoro(1-6C)alkyl,cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy,cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy,(3-6C)cycloalkyl, hetAr⁴ or Ar⁴; R⁵ is H, halogen, or (1-6C)alkyl; andAr¹, Ar², hetAr², hetAr⁴ and Ar⁴ are as defined for Formula I.

In one embodiment of Formula I-a, R^(a), R^(b), R^(c) and R^(d) arehydrogen; R² is hydrogen; R¹ is (1-3C alkoxy)(1-6C)alkyl,difluoro(1-6C)alkyl, or trifluoro(1-6C)alkyl; R³ is Ar², hetAr² or(1-6C)alkyl; R⁴ is hetAr⁴ or Ar⁴; R⁵ is H, halogen, or (1-6C)alkyl; andAr¹, Ar², hetAr², hetAr⁴ and Ar⁴ are as defined for Formula I.

In one embodiment of Formula I-a, R⁴ is (1-6C)alkyl,trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4Calkoxy)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr⁴ or Ar⁴; and R^(a), R^(b),R^(c), R^(d), R¹, R², R³, hetAr⁴ and Ar⁴ are as defined for Formula I.

In one embodiment of Formula I-a, R⁴ is (1-6C)alkyl,trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4Calkoxy)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr⁴ or Ar⁴; R³ is H,(1-6C)alkyl or Ar²; and R^(a), R^(b), R^(c), R^(d), R¹, R², hetAr⁴, Ar⁴and Ar² are as defined for Formula I.

In one embodiment of Formula I-a, R⁴ is (1-6C)alkyl,trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4Calkoxy)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr⁴ or Ar⁴; R³ is H,(1-6C)alkyl or Ar²; R⁵ is H, (1-6C)alkyl, or halogen; and R^(a), R^(b),R^(c), R^(d), R¹, R², hetAr⁴, Ar⁴ and Ar² are as defined for Formula I.

In another embodiment of the present invention there is provided acompound according to Formula I, which is designated as Formula I-bwherein:

X is O:

B is hetAr¹;

Y is a bond;

Ring C is formula C-1:

R⁴ is H, OH, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl,cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl,(1-3C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl,hydroxycarbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar³(1-6C)alkyl,(1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy,trifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxy,cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy,amino(2-6C)alkoxy, aminocarbonyl(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy, hetCyc²(1-6C)alkoxy, hetAr³(1-6C)alkoxy, Ar³(1-6C)alkoxy,(1-4C alkoxy)(1-6C)alkoxy, (1-3C alkylsulfonyl)(1-6C)alkoxy,(3-6C)cycloalkyl, hetAr⁴, or Ar⁴;

R⁵ is H, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl,halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl,(1-4C alkyl)OC(═O)—, or phenyl optionally substituted with one or moregroups independently selected from halogen, (1-6C)alkyl and(1-6C)alkoxy; and R^(a), R^(b), R^(c), R^(d), R¹, R², hetAr¹, R³,hetCyc², hetAr³, Ar³, hetAr⁴, and Ar⁴ are as defined for Formula I.

In one embodiment of Formula I-b, R^(a), R^(b), R^(c) and R^(d) arehydrogen; R² is hydrogen; and R¹, hetAr¹, R³, hetCyc², hetAr³, Ar³,hetAr⁴, and Ar⁴ are as defined for Formula I.

In one embodiment of Formula I-b, R^(a), R^(b), R^(c) and R^(d) arehydrogen; R² is hydrogen; R¹ is (1-3C alkoxy)(1-6C)alkyl,difluoro(1-6C)alkyl, or trifluoro(1-6C)alkyl; and hetAr¹, R³, hetCyc²,hetAr³, Ar³, hetAr⁴, and Ar⁴ are as defined for Formula I.

In one embodiment of Formula I-b, R^(a), R^(b), R^(c) and R^(d) arehydrogen; R² is hydrogen; R¹ is (1-3C alkoxy)(1-6C)alkyl,difluoro(1-6C)alkyl, or trifluoro(1-6C)alkyl; R³ is Ar², hetAr² or(1-6C)alkyl; and hetAr¹, Ar², hetAr², hetCyc², hetAr³, Ar³, hetAr⁴, andAr⁴ are as defined for Formula I.

In one embodiment of Formula I-b, R^(a), R^(b), R^(c) and R^(d) arehydrogen; R² is hydrogen; R¹ is (1-3C alkoxy)(1-6C)alkyl,difluoro(1-6C)alkyl, or trifluoro(1-6C)alkyl; R³ is Ar², hetAr² or(1-6C)alkyl; R⁴ is H, (1-6C)alkyl, trifluoro(1-6C)alkyl,cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy,cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy,(3-6C)cycloalkyl, hetAr⁴ or Ar⁴; and hetAr¹, Ar², hetAr², hetCyc²,hetAr³, hetAr⁴ and Ar⁴ are as defined for Formula I.

In one embodiment of Formula I-b, R^(a), R^(b), R^(c) and R^(d) arehydrogen; R² is hydrogen; R¹ is (1-3C alkoxy)(1-6C)alkyl,difluoro(1-6C)alkyl, or trifluoro(1-6C)alkyl; R³ is Ar², hetAr² or(1-6C)alkyl; R⁴ is H, (1-6C)alkyl, trifluoro(1-6C)alkyl,cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy,cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy,(3-6C)cycloalkyl, hetAr⁴ or Ar⁴; R⁵ is H, halogen, CN, (1-6C)alkyl,(1-4C)alkoxy, hydroxy(1-4C)alkyl, or phenyl optionally substituted withone or more groups independently selected from halogen, (1-6C)alkyl and(1-6C)alkoxy; and hetAr¹, Ar², hetAr², hetCyc², hetAr³, hetAr⁴ and Ar⁴are as defined for Formula I.

In one embodiment of Formula I-b, R^(a), R^(b), R^(c) and R^(d) arehydrogen; R² is hydrogen; R¹ is (1-3C alkoxy)(1-6C)alkyl,difluoro(1-6C)alkyl, or trifluoro(1-6C)alkyl; R³ is Ar², hetAr² or(1-6C)alkyl; R⁴ is H, (1-6C)alkyl, trifluoro(1-6C)alkyl,cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy,cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy,(3-6C)cycloalkyl, hetAr⁴ or Ar⁴; R⁵ is H, halogen, or (1-6C)alkyl; andhetAr¹, Ar², hetAr², hetAr³, hetAr⁴ and Ar⁴ are as defined for FormulaI.

In one embodiment of Formula I-b, R⁴ is (1-6C)alkyl,trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4Calkoxy)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr⁴ or Ar⁴; and R^(a), R^(b),R^(c), R^(d), R¹, R², R³, hetAr⁴ and Ar⁴ are as defined for Formula I.

In one embodiment of Formula I-b, R⁴ is (1-6C)alkyl,trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4Calkoxy)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr⁴ or Ar⁴; R³ is H,(1-6C)alkyl or Ar²; and R^(a), R^(b), R^(c), R^(d), R¹, R², hetAr⁴, Ar⁴and Ar² are as defined for Formula I.

In one embodiment of Formula I-b, R⁴ is hetAr⁴ or Ar⁴; R³ is H,(1-6C)alkyl or Ar²; R⁵ is H, (1-6C)alkyl, or halogen; and R^(a), R^(b),R^(c), R^(d), R¹, R² hetAr⁴, Ar⁴ and Ar² are as defined for Formula I.

In another embodiment of the present invention there is provided acompound according to Formula I, which is designated as Formula I-cwherein:

X is O:

B is Ar¹;

Y is a bond;

Ring C is formula C-1:

R⁴ and R⁵ together with the atoms to which they are attached form a 5-6membered saturated, partially unsaturated or saturated carbocyclic ringoptionally substituted with one or more substituents independentlyselected from (1-6C)alkyl, or R⁴ and R⁵ together with the atoms to whichthey are attached form a 5-6 membered saturated, partially unsaturatedor saturated heterocyclic ring having a ring heteroatom selected from N,O or S, wherein said heterocyclic ring is optionally substituted with(1-6C alkyl)C(═O)O—, or (1-6)acyl, and said sulfur ring atom isoptionally oxidized to S(═O) or SO₂; wherein R^(a), R^(b), R^(c), R^(d),R¹, R², Ar¹ and R³ are as defined for Formula I.

In one embodiment of Formula I-c, R⁴ and R⁵ together with the atoms towhich they are attached form a 5-6 membered saturated carbocyclic ringoptionally substituted with one or more substituents independentlyselected from (1-6C)alkyl, or R⁴ and R⁵ together with the atoms to whichthey are attached form a 5-6 membered saturated heterocyclic ring havinga ring heteroatom selected from N, O or S, wherein said ring nitrogenatom is optionally substituted with (1-6C alkyl)C(═O)O—, or (1-6)acyl,and said sulfur ring atom is optionally oxidized to S(═O) or SO₂;wherein R^(a), R^(b), R^(c), R^(d), R¹, R², Ar¹ and R³ are as definedfor Formula I.

In one embodiment of Formula I-c, R^(a), R^(b), R^(c), R^(d) and R² arehydrogen; and R¹, Ar¹ and R³ are as defined for Formula I.

In one embodiment of Formula I-c, R^(a), R^(b), R^(c), R^(d) and R² arehydrogen; R¹ is (1-3C alkoxy)(1-6C)alkyl, (trifluoromethoxy)(1-6C)alkyl,(1-3C sulfanyl)(1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, or(1-3Calkylamino)(1-3C)alkyl; and Ar¹ and R³ are as defined for FormulaI.

In one embodiment of Formula I-c, R^(a), R^(b), R^(c), R^(d) and R² arehydrogen; R¹ is (1-3C alkoxy)(1-6C)alkyl, (trifluoromethoxy)(1-6C)alkyl,(1-3C sulfanyl)(1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, or(1-3Calkylamino)(1-3C)alkyl; R³ is H, (1-6C)alkyl or phenyl optionallysubstituted with one or more groups independently selected from halogen,(1-6C)alkyl and hydroxymethyl; and Ar¹ is as defined for Formula I.

In one embodiment of Formula I-c, R^(a), R^(b), R^(c), R^(d) and R² arehydrogen; R¹ is (1-3C alkoxy)(1-6C)alkyl, (trifluoromethoxy)(1-6C)alkyl,(1-3C sulfanyl)(1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, or(1-3Calkylamino)(1-3C)alkyl; R³ is phenyl optionally substituted withone or more groups independently selected from halogen, (1-6C)alkyl andhydroxymethyl; and Ar¹ is as defined for Formula I.

In another embodiment of the present invention there is provided acompound according to Formula I, which is designated as Formula I-d,wherein:

X is O:

B is hetAr¹;

Y is a bond;

Ring C is formula C-1:

R⁴ and R⁵ together with the atoms to which they are attached form a 5-6membered saturated, partially unsaturated or saturated carbocyclic ringoptionally substituted with one or more substituents independentlyselected from (1-6C)alkyl, or R⁴ and R⁵ together with the atoms to whichthey are attached form a 5-6 membered saturated, partially unsaturatedor saturated heterocyclic ring having a ring heteroatom selected from N,O or S, wherein said heterocyclic ring is optionally substituted with(1-6C alkyl)C(═O)O—, or (1-6)acyl, and said sulfur ring atom isoptionally oxidized to S(═O) or SO₂; wherein R^(a), R^(b), R^(c), R^(d),R¹, R², Ar¹ and R³ are as defined for Formula I.

In one embodiment of Formula I-d, R⁴ and R⁵ together with the atoms towhich they are attached form a 5-6 membered saturated carbocyclic ringoptionally substituted with one or more substituents independentlyselected from (1-6C)alkyl, or R⁴ and R⁵ together with the atoms to whichthey are attached form a 5-6 membered saturated heterocyclic ring havinga ring heteroatom selected from N, O or S, wherein said ring nitrogenatom is optionally substituted with (1-6C alkyl)C(═O)O—, or (1-6)acyl,and said sulfur ring atom is optionally oxidized to S(═O) or SO₂;wherein R^(a), R^(b), R^(c), R^(d), R¹, R², hetAr¹ and R³ are as definedfor Formula I.

In one embodiment of Formula I-d, R^(a), R^(b), R^(c), R^(d) and R² arehydrogen; and R¹, hetAr¹ and R³ are as defined for Formula I.

In one embodiment of Formula I-d, R^(a), R^(b), R^(c), R^(d) and R² arehydrogen; R¹ is (1-3C alkoxy)(1-6C)alkyl, (trifluoromethoxy)(1-6C)alkyl,(1-3C sulfanyl)(1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, or(1-3Calkylamino)(1-3C)alkyl; and hetAr¹ and R³ are as defined forFormula I.

In one embodiment of Formula I-d, R^(a), R^(b), R^(c), R^(d) and R² arehydrogen; R¹ is (1-3C alkoxy)(1-6C)alkyl, (trifluoromethoxy)(1-6C)alkyl,(1-3C sulfanyl)(1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, or(1-3Calkylamino)(1-3C)alkyl; R³ is H, (1-6C)alkyl or phenyl optionallysubstituted with one or more groups independently selected from halogen,(1-6C)alkyl and hydroxymethyl; and hetAr¹ is as defined for Formula I.

In one embodiment of Formula I-d, R^(a), R^(b), R^(c), R^(d) and R² arehydrogen; R¹ is (1-3C alkoxy)(1-6C)alkyl, (trifluoromethoxy)(1-6C)alkyl,(1-3C sulfanyl)(1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, or(1-3Calkylamino)(1-3C)alkyl; R³ is phenyl optionally substituted withone or more groups independently selected from halogen, (1-6C)alkyl andhydroxymethyl; and hetAr¹ is as defined for Formula I.

As noted, the Y—B moiety and the —NH—C(═X)—NH— moiety of Formula I arein trans configuration on the pyrrolidine ring, which relativestereochemistry can be illustrated by either formula A or B:

in which the straight thick bars (

) and straight dashed bars (

) indicate relative stereochemistry. In one embodiment of the aboveFormulas A and B, Y is a bond and B is Ring B, wherein Ring B is Ar¹ orhetAr¹.

In one embodiment of Formula I, the Y—B and the —NH—C(═X)—NH— moietiesare trans in the absolute configuration which can be illustrated byformulas C and D:

in which the solid wedges (

) and dashed wedges (

) indicate absolute stereochemistry. In one embodiment of the aboveFormulas C and D, Y is a bond and B is Ring B, wherein Ring B is Ar¹ orhetAr¹.

It will be appreciated that certain compounds according to the inventionmay contain one or more centers of asymmetry and may therefore beprepared and isolated in a mixture of isomers such as a racemic mixture,or in an enantiomerically pure form.

It will further be appreciated that the compounds of Formula I or theirsalts may be isolated in the form of solvates, and accordingly that anysuch solvate is included within the scope of the present invention. Forexample, compounds of Formula I can exist in unsolvated as well assolvated forms with pharmaceutically acceptable solvents such as water,ethanol, and the like.

The compounds of Formula I include pharmaceutically acceptable saltsthereof. In addition, the compounds of Formula I also include othersalts of such compounds which are not necessarily pharmaceuticallyacceptable salts, and which may be useful as intermediates for preparingand/or purifying compounds of Formula I and/or for separatingenantiomers of compounds of Formula I. Particular examples of saltsinclude hydrochloride salts.

The term “pharmaceutically acceptable” indicates that the substance orcomposition is compatible chemically and/or toxicologically, with theother ingredients comprising a formulation, and/or the mammal beingtreated therewith.

The present invention also provides a process for the preparation of acompound of Formula I or a salt thereof as defined herein, whichcomprises:

(a) for a compound of Formula I where X is O, coupling a correspondingcompound having the formula II

with a corresponding compound having the formula III

in the presence carbonyldiimidazole or triphosgene and a base; or

(b) for a compound of Formula I where X is S, coupling a correspondingcompound having the formula II

with a corresponding compound having the formula III

in the presence di(1H-imidazol-2-yl)methanethione and a base; or

(c) for a compound of Formula I where X is O, coupling a correspondingcompound having the formula II

with a corresponding compound having the formula IV

where L¹ is a leaving group, in the presence of a base; or

(d) for a compound of Formula I where X is O, coupling a correspondingcompound having the formula V

where L² is a leaving group, with a corresponding compound having theformula III

in the presence of a base; or

(e) for a compound of Formula I where X is O, activating a correspondingcompound having the formula VI

with diphenylphosphoryl azide followed by coupling the activatedintermediate with a corresponding compound having the formula III

in the presence a base; or

(f) for a compound of Formula I where X is O, coupling a correspondingcompound having the formula II

with a corresponding compound having the formula VII

in the presence of a base; or

(g) for a compound of Formula I where R¹ is(trifluoromethoxy)(1-6C)alkyl, (1-3C sulfanyl)(1-6C)alkyl,monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl,tetrafluoro(2-6C)alkyl, or pentafluoro(2-6C)alkyl, reacting acorresponding compound having the formula VIII

with a corresponding compound having the(trifluoromethoxy)(1-6C)alkyl-L³, (1-3C sulfanyl)(1-6C)alkyl-L³,monofluoro(1-6C)alkyl-L³, difluoro(1-6C)alkyl-L³,trifluoro(1-6C)alkyl-L³, tetrafluoro(2-6C)alkyl-L³, orpentafluoro(2-6C)alkyl-L³, where L³ is a leaving atom or a leavinggroup, in the presence of a base; or

(h) for a compound of Formula I where X is O, R⁴ is CH₃OCH₂— and R⁵ isOHCH₂—, treating a corresponding compound having the general formula IX

with an inorganic acid; and

optionally removing protecting groups and optionally preparing apharmaceutically acceptable salt thereof.

In the above methods, the term “corresponding” means that thedefinitions for the “corresponding compound” are as defined for FormulaI unless stated otherwise.

In one embodiment of any of the above methods, Y is a bond and B is RingB, where Ring B is Ar¹ or hetAr¹ as defined for Formula I.

Referring to method (a), the base may be an amine base, such astriethylamine or diisopropylamine. Suitable solvents includedichloromethane, dichloroethane, THF, DMA and DMF. The reaction isconveniently performed at ambient temperature.

Referring to method (b), the base may be an amine base, such astriethylamine or diisopropylamine. Suitable solvents includedichloromethane, dichloroethane, THF, DMA and DMF. The reaction isconveniently performed at ambient temperature.

Referring to method (c), the leaving group may be, for example, phenoxyor 4-nitrophenoxy. The base may be an amine base, such as triethylamineor diisopropylamine. Suitable solvents include DMA, DMF and DCE. Thereaction is conveniently performed at ambient temperature.

Referring to method (d), the leaving group may be, for example, phenoxyor 4-nitrophenoxy. The base may be an amine base, such as triethylamineor diisopropylamine. Suitable solvents include DCE, DMA and DMF. Thereaction is conveniently performed at ambient temperature.

Referring to method (e), the base may be an amine base, such astriethylamine or diisopropylamine. Suitable solvents include toluene andDMF. The reaction is conveniently performed at elevated temperatures,for example the reflux temperature of the solvent.

Referring to method (f), the base may be an amine base, such astriethylamine or diisopropylamine. Suitable solvents include DCM, DCE,DMF and THF. The reaction is conveniently performed at temperaturesbetween about 0° C. and ambient temperature.

A compound of Formula VII may be prepared by reacting a compound ofFormula III with bis(trichloromethyl) carbonate in the presence of abase, such as an amine base.

Referring to method (g), the base may be an amine base, such astriethylamine or diisopropylamine. Suitable solvents include DMF, DMAand THF. The reaction is conveniently performed at temperatures betweenambient temperature and 60° C.

Referring to method (h), the acid may be, for example, hydrochloricacid. Suitable solvents include DCM. The reaction is convenientlyperformed at ambient temperature.

Amine groups in compounds described in any of the above methods may beprotected with any convenient amine protecting group, for example asdescribed in Greene & Wuts, eds., “Protecting Groups in OrganicSynthesis”, 2^(nd) ed. New York; John Wiley & Sons, Inc., 1991. Examplesof amine protecting groups include acyl and alkoxycarbonyl groups, suchas t-butoxycarbonyl (BOC), phenoxycarbonyl, and[2-(trimethylsilyl)ethoxy]methyl (SEM). Likewise, carboxyl groups may beprotected with any convenient carboxyl protecting group, for example asdescribed in Greene & Wuts, eds., “Protecting Groups in OrganicSynthesis”, 2^(nd) ed. New York; John Wiley & Sons, Inc., 1991. Examplesof carboxyl protecting groups include (1-6C)alkyl groups, such asmethyl, ethyl and t-butyl. Alcohol groups may be protected with anyconvenient alcohol protecting group, for example as described in Greene& Wuts, eds., “Protecting Groups in Organic Synthesis”, 2^(nd) ed. NewYork; John Wiley & Sons, Inc., 1991. Examples of alcohol protectinggroups include benzyl, trityl, silyl ethers, and the like.

The compounds of the formulas II, III, III, IV, V, VI, VII, VIII, and IXare also believed to be novel and are provided as further aspects of theinvention.

In one embodiment of the above-described processes (a), (b), (c), and(f), where B is Ar¹ and R^(a), R^(b), R^(c), R^(d) and R² are hydrogen,a single enantiomer of intermediate II, namely enantiomer 1 of II-A isprepared by chiral crystallization prior to use. Accordingly, in oneembodiment, a process for preparing enantiomer 1 of II-A comprises:

preparing racemic trans II-A

where Ring B and the NH₂ group are in the trans configuration; Ring B isRing B is Ar¹ or hetAr¹; Ar¹ is phenyl optionally substituted with oneor more substituents independently selected from halogen, CF₃, CF₃O—,(1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-6C)alkyl and CN; and hetAr¹ is a5-6 membered heteroaryl having 1-3 ring heteroatoms independentlyselected from N, S and O, and optionally substituted with 1-2 groupsindependently selected form (1-6C)alkyl, halogen, OH, CF₃, NH₂ andhydroxy(1-2C)alkyl; said method comprising:

treating racemic trans II-A with di-p-toluoyl-D-tartaric acid to providethe di-p-toluoyl-D-tartaric acid salt of racemic trans II-A;

recrystallizing the di-p-toluoyl-D-tartaric acid salt of trans II-A toprovide the di-p-toluoyl-D-tartaric acid salt of enantiomer 1 of transII-A; and

treating the di-p-toluoyl-D-tartaric acid salt of enantiomer 1 of transII-A with an inorganic base to provide free base of enantiomer 1 oftrans II-A having the absolute configuration as illustrated:

In one embodiment of racemic trans II-A, R¹ is 2-methoxyethoxy and RingB is 4-fluorophenyl, and racemic trans II-A is prepared by the processcomprising:

reacting 4-fluorobenzaldehyde with nitromethane in the presence ofacetic acid and ammonium acetate to provide(E)-1-fluoro-4-(2-nitrovinyl)benzene

reacting (E)-1-fluoro-4-(2-nitrovinyl)benzene with2-methoxy-N-(methoxymethyl)-N-((trimethylsilyl)methyl)ethanamine in thepresence of a catalytic amount of an acid (such as TFA) to providetrans-3-(4-fluorophenyl)-1-(2-methoxyethyl)-4-nitropyrrolidine

treating trans-3-(4-fluorophenyl)-1-(2-methoxyethyl)-4-nitropyrrolidinewith platinum (IV) oxide or Raney Nickel in a hydrogen atmosphere toprovide trans-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine

wherein the 4-fluorophenyl and amino group are in the transconfiguration.

In one embodiment, the inorganic base is an alkali metal hydroxide suchas sodium hydroxide.

A similar process as above may be used utilizing di-p-toluoyl-L-tartricacid to provide enantiomer 2 of II-A:

The ability of compounds of the invention to act as TrkA inhibitors maybe demonstrated by the assay described in Example A.

Compounds of Formula I are useful for treating pain, including chronicand acute pain. For example, compounds of Formula I may be useful in thetreatment of multiple types of pain including inflammatory pain,neuropathic pain, and pain associated with cancer, surgery, and bonefracture.

In one embodiment, compounds of Formula I are useful for treating acutepain. Acute pain, as defined by the International Association for theStudy of Pain, results from disease, inflammation, or injury to tissues.This type of pain generally comes on suddenly, for example, after traumaor surgery, and may be accompanied by anxiety or stress. The cause canusually be diagnosed and treated, and the pain is confined to a givenperiod of time and severity. In some instances, it can become chronic.

In one embodiment, compounds of Formula I are useful for treatingchronic pain. Chronic pain, as defined by the International Associationfor the Study of Pain, is widely believed to represent disease itself.It can be made much worse by environmental and psychological factors.Chronic pain persists over a longer period than acute pain and isresistant to most medical treatments, generally over 3 months or more.It can and often does cause severe problems for patients.

Compounds of Formula I are also useful for treating cancer. Particularexamples include neuroblastoma, ovarian, pancreatic, colorectal andprostate cancer.

Compounds of Formula I are also useful for treating inflammation andcertain infectious diseases.

In addition, compounds of Formula I may also be used to treatinterstitial cystitis (IC), painful bladder syndrome (PBS), urinaryincontinence, asthma, anorexia, atopic dermatitis, and psoriasis.

Compounds of Formula I are also useful for treating a neurodegenerativedisease in a mammal, comprising administering to said mammal one or morecompounds of Formula I or a pharmaceutically acceptable salt thereof inan amount effective to treat or prevent said neurodegenerative disease.In one embodiment, compounds of Formula I may also be used to treatdemyelination and dysmyelination by promoting myelination, neuronalsurvival, and oligodendrocyte differentiation via blocking Sp35-TrkAinteraction. In one embodiment, the neurodegenerative disease ismultiple sclerosis. In one embodiment, the neurodegenerative disease isParkinson's disease. In one embodiment, the neurodegenerative disease isAlzheimer's disease.

As used herein, terms “treat” or “treatment” refer to therapeutic orpalliative or measures. Beneficial or desired clinical results include,but are not limited to, alleviation, in whole or in part, of symptomsassociated with a disorder or condition, diminishment of extent ofdisease, stabilized (i.e., not worsening) state of disease, delay orslowing of disease progression, amelioration or palliation of thedisease state, and remission (whether partial or total), whetherdetectable or undetectable. “Treatment” can also mean prolongingsurvival as compared to expected survival if not receiving treatment.

In certain embodiments, compounds of Formula I are useful for preventingdiseases and disorders as defined herein. The term “preventing” as usedherein means the prevention of the onset, recurrence or spread, in wholeor in part, of the disease or condition as described herein, or asymptom thereof.

Accordingly, one embodiment of this invention provides a method oftreating pain in a mammal, comprising administering to said mammal oneor more compounds of Formula I or a pharmaceutically acceptable saltthereof in an amount effective to treat or prevent said pain. In oneembodiment, the pain is chronic pain. In one embodiment, the pain isacute pain. In one embodiment, the pain is inflammatory pain,neuropathic pain, and pain associated with cancer, surgery, and bonefracture.

Another embodiment of this invention provides a method of treatinginflammation in a mammal, comprising administering to said mammal one ormore compounds of Formula I or a pharmaceutically acceptable saltthereof in an amount effective to treat or prevent said inflammation.

Another embodiment of this invention provides a method of treating aneurodegenerative disease in a mammal, comprising administering to saidmammal one or more compounds of Formula I or a pharmaceuticallyacceptable salt thereof in an amount effective to treat or prevent saidneurodegenerative disease.

Another embodiment of this invention provides a method of treatingTrypanosoma cruzi infection in a mammal, comprising administering tosaid mammal one or more compounds of Formula I or a pharmaceuticallyacceptable salt thereof in an amount effective to treat or prevent saidTrypanosoma cruzi infection.

The phrase “effective amount” means an amount of compound that, whenadministered to a mammal in need of such treatment, is sufficient to (i)treat or prevent a particular disease, condition, or disorder which canbe treated with a compound of Formula I, (ii) attenuate, ameliorate, oreliminate one or more symptoms of the particular disease, condition, ordisorder, or (iii) prevent or delay the onset of one or more symptoms ofthe particular disease, condition, or disorder described herein.

The amount of a compound of Formula I that will correspond to such anamount will vary depending upon factors such as the particular compound,disease condition and its severity, the identity (e.g., weight) of themammal in need of treatment, but can nevertheless be routinelydetermined by one skilled in the art.

As used herein, the term “mammal” refers to a warm-blooded animal thathas or is at risk of developing a disease described herein and includes,but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters,and primates, including humans.

The compounds of the present invention can be used in combination withone or more additional drugs that work by the same or a differentmechanism of action. Examples include anti-inflammatory compounds,steroids (e.g., dexamethasone, cortisone and fluticasone), analgesicssuch as NSAIDs (e.g., aspirin, ibuprofen, indomethacin, and ketoprofen),and opioids (such as morphine), and chemotherapeutic agents.

Compounds of the invention may be administered by any convenient route,e.g. into the gastrointestinal tract (e.g. rectally or orally), thenose, lungs, musculature or vasculature, or transdermally or dermally.Compounds may be administered in any convenient administrative form,e.g. tablets, powders, capsules, solutions, dispersions, suspensions,syrups, sprays, suppositories, gels, emulsions, patches etc. Suchcompositions may contain components conventional in pharmaceuticalpreparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulkingagents, and further active agents. If parenteral administration isdesired, the compositions will be sterile and in a solution orsuspension form suitable for injection or infusion. Such compositionsform a further aspect of the invention. An example of a suitable oraldosage form is a tablet containing about 25 mg, 50 mg, 100 mg, 250 mg,or 500 mg of the compound of the invention compounded with about 90-30mg anhydrous lactose, about 5-40 mg sodium croscarmellose, about 5-30 mgpolyvinylpyrrolidone (“PVP”) K30, and about 1-10 mg magnesium stearate.The powdered ingredients are first mixed together and then mixed with asolution of the PVP. The resulting composition can be dried, granulated,mixed with the magnesium stearate and compressed to tablet form usingconventional equipment. An aerosol formulation can be prepared bydissolving the compound, for example 5-400 mg, of the invention in asuitable buffer solution, e.g. a phosphate buffer, adding a tonicifier,for example a salt such sodium chloride, if desired. The solution istypically filtered, for example using a 0.2 micron filter, to removeimpurities and contaminants.

Another formulation may be prepared by mixing a compound describedherein and a carrier or excipient. Suitable carriers and excipients arewell known to those skilled in the art and are described in detail in,e.g., Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms andDrug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins,2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice ofPharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe,Raymond C. Handbook of Pharmaceutical Excipients. Chicago,Pharmaceutical Press, 2005. The formulations may also include one ormore buffers, stabilizing agents, surfactants, wetting agents,lubricating agents, emulsifiers, suspending agents, preservatives,antioxidants, opaquing agents, glidants, processing aids, colorants,sweeteners, perfuming agents, flavoring agents, diluents and other knownadditives to provide an elegant presentation of the drug (i.e., acompound described herein or pharmaceutical composition thereof) or aidin the manufacturing of the pharmaceutical product (i.e., medicament).

Accordingly, another aspect of the present invention provides apharmaceutical composition, which comprises a compound of Formula I or apharmaceutically acceptable salt thereof, as defined hereinabove,together with a pharmaceutically acceptable diluent or carrier.

According to another embodiment, the present invention provides acompound of Formula I or a pharmaceutically acceptable salt thereof, foruse in the treatment of pain in a mammal. In one embodiment, the pain ischronic pain. In one embodiment the pain is acute pain. In oneembodiment, the pain is inflammatory pain, neuropathic pain, and painassociated with cancer, surgery, and bone fracture.

In another embodiment, the present invention provides a compound ofFormula I or a pharmaceutically acceptable salt thereof, for use in thetreatment of inflammation in a mammal.

In another embodiment, the present invention provides a compound ofFormula I or a pharmaceutically acceptable salt thereof, for use in thetreatment of infectious diseases, for example Trypanosoma cruziinfection, in a mammal.

In another embodiment, the present invention provides a compound ofFormula I or a pharmaceutically acceptable salt thereof, for use in thetreatment of a neurodegenerative disease in a mammal.

According to a further aspect, the present invention provides the use ofa compound of Formula I or a pharmaceutically acceptable salt thereof,in the manufacture of a medicament for the treatment of a conditionselected from pain, cancer, inflammation, neurodegenerative disease orTrypanosoma cruzi infection. In one embodiment, the condition is chronicpain. In one embodiment, the condition is acute pain. In one embodiment,the pain is inflammatory pain, neuropathic pain, and pain associatedwith cancer, surgery, and bone fracture. In one embodiment, thecondition is cancer. In one embodiment, the condition is inflammation.In one embodiment, the condition is a neurodegenerative disease. In oneembodiment, the condition is Trypanosoma cruzi infection.

Abbreviations used in herein have the following definitions:

CDI Carbonyl diimidazole DCE Dichloroethane DCM Dichloromethane DIEADiisopropylethylamine DMA N,N-Dimethylacetamide DMFN,N-Dimethylformamide DPPA Diphenylphosphorylazide HATU(2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3- tetramethyluroniumhexafluorophosphate) MP-TsOH Polymer supported p-toluenesulfonic acid(Macroporous Polystyrene resin containing p-toluenesulfonic acid(Purchased from Biotage) MsCl Methanesulfonyl chloride PS-DMAPPolystyrene bound dimethyl aminopyridine (Purchased from Biotage) TFATrifluoroacetic acid

EXAMPLES

The following examples illustrate the invention. In the examplesdescribed below, unless otherwise indicated all temperatures are setforth in degrees Celsius. Reagents were purchased from commercialsuppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge,and were used without further purification unless otherwise indicated.THF, DCM, toluene, DMF and dioxane were purchased from Aldrich inSure/Seal™ bottles and used as received.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried.

Column chromatography was done on a Biotage system (Manufacturer: DyaxCorporation) having a silica gel or C-18 reverse phase column, or on asilica SepPak cartridge (Waters).

Biological Assay Example A TrkA Omnia Assay

Trk enzymatic selectivity was assessed using Omnia™ Kinase Assayreagents from Invitrogen Corp. Enzyme (TrkA from Invitrogen Corp.) andtest compound (various concentrations) were incubated for 10 minutes atambient temperature in a 384-well white polypropylene plate (Nunccatalog#267462). Omnia Tyr Peptide #4, as well as ATP, were then addedto the plate. Final concentrations were as follows: 20 nM enzyme, 500 μMof ATP, 10 μM peptide substrate. The assay buffer consisted of 25 mMMOPS pH 7.5, 0.005% (v/v) Triton X-100 and 5 mM MgCl₂. The production ofphosphorylated peptide was monitored continuously for 70 minutes using aMolecular Devices FlexStation II³⁸⁴ microplate reader (excitation=360nm; emission=485 nm). Initial rates were calculated from the progresscurves. IC₅₀ values were calculated from these rates using either a 4 or5-parameter logistic curve fit.

Compounds of the invention had an average IC₅₀ value below 1000 nM whentested in this assay. Certain compounds had an average IC₅₀ value below100 nM when tested in this assay.

Table A provides averaged IC₅₀ values for compounds of the inventionwhen tested in the assay of Example A, where A represents an averagedIC₅₀ value <100 nM; B represents an averaged IC₅₀ value from 100 to1,000 nM; and C represents an averaged IC₅₀ value from 1,000 to 10,000nM.

TABLE A TrkA Enzyme Ex. # IC₅₀ 1 A 2 C 3 A 4 A 5 C 6 C 7 C 8 B 9 A 10 A11 A 12 A 13 A 14 A 15 B 16 C 17 B 18 A 19 B 20 C 21 A 22 A 23 A 24 A 25B 26 A 27 C 28 B 29 C 30 A 31 B 32 B 33 B 34 C 35 C 36 A 37 A 38 A 39 A40 A 41 A 42 A 43 B 44 A 45 C 46 C 47 B 48 B 49 C 50 A 51 A 52 A 53 A 54C 55 B 56 A 57 A 58 A 59 A 60 A 61 A 62 A 63 A 64 A 65 A 66 A 67 B 68 C69 Example 69 omitted 70 A 71 A 72 A 73 A 74 A 75 A 76 A 77 A 78 A 79 C80 A 81 A 82 A 83 A 84 A 85 A 86 A 87 A 88 A 89 A 90 A 91 A 92 A 93 A 94B 95 A 96 A 97 A 98 A 99 A 100 B 101 A 102 A 103 A 104 A 105 A 106 B 107A 108 A 109 B 110 A 111 A 112 A 113 A 114 A 115 A 116 A 117 A 118 A 119A 120 A 121 A 122 B 123 A 124 A 125 A 126 A 127 A 128 A 129 A 130 A 131A 132 A 133 A 134 A 135 A 136 B 137 A 138 A 139 A 140 A 141 A 142 A 143A 144 A 145 A 146 A 147 A 148 A 149 A 150 A 151 A 152 A 153 B 154 C 155A 156 A 157 A 158 C 159 B 160 B 161 A 162 A 163 A 164 A 165 A 166 A 167A 168 A 169 A 170 A 171 A 172 A 173 A 174 A 175 A 176 A 177 A 178 A 179A 180 C 181 B 182 A 183 B 184 C 185 B 186 A 187 B 188 B 189 B 190 C 191B 192 B 193 B 194 A 195 A 196 A 197 A 198 A 199 A 200 B 201 B 202 A 203B 204 A 205 A 206 B 207 B 208 B 209 B 210 A 211 A 212 C 213 B 214 A 215A 216 A 217 A 218 A 219 A 220 B 221 A 222 A 223 A 224 A 225 A 226 A 227A 228 A 229 A 230 B 231 A 232 B 233 B 234 B 235 B 236 B 237 B 238 B 239B 240 B 241 B 242 A 243 A 244 A 245 B 246 A 247 B 248 A 249 A 250 A 251A 252 A 253 B 254 A 255 A 256 B 257 B 258 A 259 A 260 A 261 B 262 C 263A 264 A 265 A 266 A 267 A 268 A 269 A 270 A 271 A 272 A 273 B 274 B 275B 276 A 277 A 278 A 279 B 280 A 281 A 282 A 283 A 284 A 285 A 286 A 287A 288 A 289 A 290 A 291 A 292 A 293 A 294 A 295 A 296 A 297 A 298 A 299A 300 A 301 A 302 A 303 A 304 A 305 A 306 A 307 A 308 A 309 A 310 B 311A 312 A 313 A 314 A 315 A 316 A 317 A 318 B 319 A 320 A 321 A 322 A 323A 324 A 325 A 326 A 327 A 328 A 329 A 330 A 331 A 332 B 333 B 334 A 335A 336 A 337 A 338 A 339 A 340 B 341 B 342 A 343 A 344 A 345 A 346 A 347A 348 A 349 A 350 A 351 A 352 A 353 B 354 B 355 A 356 A 357 A 358 A 359A 360 A 361 A 362 A 363 A 364 A 365 A 366 A 367 A 368 A 369 A 370 A 371A 372 A 373 A 374 A 375 A 376 A 377 A 378 A 379 A 380 A 381 A 382 A 383A 384 A 385 A 386 A 387 A 388 A 389 A 390 A 391 A 392 A 393 A 394 B 395B 396 A 397 A 398 A 399 A 400 B 401 A 402 B 403 A 404 A 405 A 406 A 407A 408 A 409 A 410 A 411 A 412 A 413 A 414 A 415 A 416 A 417 A 418 A 419A 420 A 421 A 422 A 423 A 424 A 425 A 426 A 427 A 428 A 429 A 430 A 431A 432 B 433 A 434 A 435 A 436 A 437 A 438 A 439 A 440 A 441 A 442 A 443A 444 A 445 A 446 A 447 A 448 A 449 A 450 A 451 A 452 A 453 A 454 A 455A 456 A 457 A 458 B 459 A 460 A 461 A 462 A 463 A 464 A 465 A 466 A 467A 468 A 469 C 470 B 471 B 472 B 473 A 474 A 475 A 476 A 477 A 478 A 479A 480 A 481 A 482 A 483 A 484 A 485 B 486 A 487 A 488 A 489 A 490 A 491A 492 A 493 A 494 A 495 A 496 B 497 B 498 A 499 A 500 A 501 A 502 A 503A 504 A 505 A 506 A 507 A 508 A 509 A 510 A 511 A 512 A 513 A 514 A 515A 516 A 517 A 518 A 519 A 520 A 521 A 522 A 523 A 524 A 525 A 526 A 527A 528 A 529 A 530 A 531 A 532 A 533 A 534 A 535 A 536 A 537 A 538 A 539B 540 A 541 A 542 A 543 A 544 A 545 A 546 A 547 A 548 B 549 A 550 A 551A 552 A 553 B 554 A 555 A 556 A 557 A 558 A 559 A 560 A 561 A 562 A 563A 564 A 565 A 566 B 567 B 568 A 569 A 570 A 571 A 572 B 573 B 574 A 575A 576 A 577 A 578 B 579 A 580 B 581 A 582 A 583 A 584 A 585 A 586 A 587A 588 A 589 B 590 A 591 A 592 A 593 A 594 A 595 A 596 A 597 A 598 A 599A 600 A 601 A 602 A 603 A 604 A 605 A 606 A 607 A 608 A 609 A 610 A 611A 612 A 613 A 614 A 615 A 616 A 617 A 618 A 619 A 620 A 621 A 622 A 623A 624 A 625 A 626 A 627 A 628 A 629 C 630 A 631 A 632 A 633 A 634 A 635A 636 B 637 A 638 A 639 A 640 A 641 B 642 B 643 A 644 A 645 A 646 B 647A 648 A 649 B

Preparation of Synthetic Intermediates Preparation A

tert-butyl trans-4-phenylpyrrolidin-3-ylcarbamate Step A: Preparation oftrans-1-benzyl-3-nitro-4-phenylpyrrolidine

To a DCM (2 L) solution of (E)-(2-nitrovinyl)benzene (149 g, 1.00 mol)was added TFA (19.5 mL, 0.250 mol), followed by cooling to −15° C. andthen slow addition of a DCM (500 mL) solution ofN-methoxymethyl-N-(trimethylsilylmethyl)benzylamine (274 g, 1.00 mol)over 3 hours, maintaining the reaction temperature between −15 and −10°C. The reaction was warmed up to ambient temperature and stirred for 18hours, then washed with 2 N NaOH (500 mL) and treated with 2 N HCl (1L). The resulting white suspension was stirred for 1 hour before beingfiltered and washed with DCM. DCM (1 L) and 2 N NaOH (750 mL) were thenadded to the collected white solid and stirred until all soliddissolved. After phase-separation, the aqueous layer was extracted withDCM (2×1 L). The combined organic layers were dried with MgSO₄, filteredand concentrated to afford the title product as an off-white solid (205g, 73% yield). MS (apci) m/z=283.1 (M+H).

Step B: Preparation of trans-1-benzyl-4-phenylpyrrolidin-3-amine

To a suspension of trans-1-benzyl-3-nitro-4-phenyl-pyrrolidine (93.9 g,333 mmol) in EtOH (1.20 L) was added concentrated HCl (450 mL), followedby addition of zinc dust (173 g, 2.66 mol) in small portions over 1.5hours while maintaining the temperature between 55-60° C. The reactionmixture was stirred at ambient temperature for 18 hours, then cooled inan ice/water bath followed by addition of concentrated NH₄OH (900 mL).The mixture (pH=10-11) was filtered and the collected zinc was washedwith CHCl₃. The filtrate was then phase-separated, and the aqueous layerwas extracted with CHCl₃ (2×400 mL). The combined organics was washedwith H₂O, brine, dried with MgSO₄, filtered and concentrated to affordthe title compound as an amber oil (85.0 g, 100% yield). MS (apci)m/z=253.2 (M+H).

Step C: Preparation oftrans-(1-benzyl-4-phenyl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester

To a mixture of trans-1-benzyl-4-phenylpyrrolidin-3-amine (85.0 g, 333mmol), THF (750 mL) and triethylamine (69.6 mL, 500 mmol), was slowlyadded (Boc)₂O (72.7 g, 333 mmol) in portions over 30 minutes. Thereaction mixture was stirred at ambient temperature for 16 hours and wasconcentrated in vacuo. The residue was dissolved in CHCl₃ and was washedwith aqueous Na₂CO₃ and brine. The organic layer was dried with MgSO₄,filtered and concentrated to afford the title compound as a pale-yellowsolid (116 g, 99% yield). MS (apci) m/z=353.0 (M+H).

Step D: Preparation of tert-butyl trans-4-phenylpyrrolidin-3-ylcarbamate

A 2 gallon Parr reactor was charged withtrans-(1-benzyl-4-phenyl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester(114 g, 323 mmol), EtOH (2 L) and 10% Pd/C (50% wet, 11.0 g). Thereactor was purged with N₂ several times, filled with H₂ to 56-57 psiand agitated at 80° C. When the reaction was complete according to HPLCanalysis, the reaction mixture was filtered and the filtrateconcentrated to provide the crude product as a yellow solid. The crudematerial was triturated from toluene to afford the title product as awhite solid (68.4 g, 78% yield). MS (apci) m/z=262.9 (M+H).

Preparation A2

trans-tert-butyl 3-amino-4-phenylpyrrolidine-1-carboxylate Step A:Preparation oftrans-N-(1-benzyl-4-phenylpyrrolidin-3-yl)-2,2,2-trifluoroacetamide

To a solution of trans-1-benzyl-4-phenylpyrrolidin-3-amine (PreparationA, Step B, 61.9 g, 245 mmol) in DCM (400 mL) was added DIEA (64.1 mL,368 mmol) and the mixture was cooled in an ice bath. Trifluoroaceticanhydride (38.1 mL, 270 mmol) was added dropwise over 30 minutes under aN₂ atmosphere. After the addition, the mixture was stirred for 30minutes and then concentrated in vacuo. The residue was dissolved in DCMand washed with saturated aqueous NaHCO₃ and brine. The solution wasdried with MgSO₄, filtered and concentrated in vacuo. The crude materialwas treated with hexanes and the resulting yellow suspension was stirredat ambient temperature for 1 hour. The solid was collected byfiltration, washed with hexanes and dried under vacuum to afford thetitle compound (78.7 g, 92% yield) as a yellow solid. MS (apci)m/z=349.1 (M+H).

Step B: Preparation oftrans-tert-butyl-3-phenyl-4-(2,2,2-trifluoroacetamido)pyrrolidine-1-carboxylate

A solution oftrans-N-(1-benzyl-4-phenylpyrrolidin-3-yl)-2,2,2-trifluoroacetamide(78.7 g, 226 mmol) in EtOH (400 mL) was purged with N₂ and treated with20% Pd(OH)₂ on activated carbon (31.7 g, 45.2 mmol). The mixture wasagitated at ambient temperature under 30 psi of H₂ in a parr reactor for7 hours, and then filtered through GF/F paper and concentrated in vacuo.The residue was dissolved in DCM (250 mL), followed by the addition ofTEA (49.4 mL, 355 mmol) and cooling in an ice bath. Boc₂O (56.8 g, 260mmol) was added slowly over 15 minutes and the reaction mixture waswarmed to ambient temperature and stirred for 1 hour. The mixture waswashed with saturated aqueous NaHCO₃ and brine, then dried with MgSO₄.The solution was filtered, concentrated and the residue was purified bysilica column chromatography eluting with 40% EtOAc/hexanes to providethe title compound as a white solid (63.2 g, 75% yield). ¹H NMR (CDCl₃)δ 7.23-7.39 (m, 5H), 6.36 (br s, 1H), 4.47-4.55 (m, 1H), 3.92-4.00 (m,1H), 3.78-4.00 (m, 1H), 3.50-3.59 (m, 1H), 3.22-3.45 (m, 2H), 1.49 (s,9H).

Step C: Preparation of trans-tert-butyl3-amino-4-phenylpyrrolidine-1-carboxylate

A solution of trans tert-butyl3-phenyl-4-(2,2,2-trifluoroacetamido)pyrrolidine-1-carboxylate (63.2 g,176 mmol) in MeOH (200 mL) was cooled in an ice bath and 2 N NaOH (220mL, 440 mmol) was added. The reaction mixture was allowed to warm toambient temperature overnight, then concentrated to approximately 200 mLand diluted with H₂O (200 mL). The aqueous mixture was extracted withDCM and the combined extracts were washed with brine and dried overNa₂SO₄. The solution was filtered and concentrated to give the titlecompound as a light yellow oil (46.2 g, 99% yield). MS (apci) m/z=163.0(M+H-Boc).

Preparation B

trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride StepA: Preparation of tert-butyltrans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-ylcarbamate

To a solution of tert-butyl trans-4-phenylpyrrolidin-3-ylcarbamate(Preparation A, 4.82 g, 17.5 mmol) in dry DMF (50 mL) was addedsequentially DIEA (9.12 mL, 52.4 mmol) and 1-bromo-2-methoxyethane (1.97mL, 20.9 mmol). The mixture was stirred at ambient temperature for 46hours and then poured into H₂O (300 mL). The mixture was extracted withEtOAc (3×150 mL) and the combined extracts were washed with brine, driedover MgSO₄/activated carbon, filtered through a SiO₂ plug capped withpacked MgSO₄, and eluted with EtOAc. The solution was concentrated anddried in vacuo yielding the product as a white solid (5.15 g, 92%yield). MS (apci) m/z=321.1 (M+H).

Step B: Preparation oftrans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride

To a solution of tert-butyltrans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-ylcarbamate (5.10 g, 15.9mmol) in 2:1 EtOAc-MeOH (150 mL) was added 4 N HCl in dioxane (59.7 mL,239 mmol). The mixture was stirred at ambient temperature for 90 minutesand then concentrated in vacuo. The resulting foam was treated withEtOAc (200 mL), sonicated for 5 minutes and stirred vigorously until afine white suspension formed. The suspension was filtered, washed withEtOAc and dried under vacuum to afford the title compound as a whitepowder (5.10 g, 100% yield). MS (apci) m/z=221.1 (M+H).

Preparation C

2-methoxy-N-(methoxymethyl)-N-((trimethylsilyl)methyl)ethanamine Step A:Preparation of 2-methoxy-N-((trimethylsilyl)methyl)ethanamine

To a DMSO solution (15 mL) of 2-methoxyethanamine (14.2 mL, 163 mmol) at90° C. was added a DMSO (10 mL) solution of(chloromethyl)trimethylsilane (11.4 mL, 81.5 mmol) by addition funnelover 40 minutes. The mixture was heated at 90° C. for 3.5 hours thencooled to ambient temperature. It was then diluted with H₂O (150 mL) andextracted with EtOAc (2×150 mL). The combined organic extracts werewashed with brine (150 mL), dried with MgSO₄, filtered and concentratedto yield the product as a yellow oil (8.14 g, 62% yield). MS (apci)m/z=162.0 (M+H).

Step B: Preparation of2-methoxy-N-(methoxymethyl)-N-((trimethylsilyl)methyl) ethanamine

A MeOH (2.45 mL) solution of formaldehyde (37% aqueous, 4.91 g, 60.6mmol) was cooled to 0° C., and treated with a dropwise addition of2-methoxy-N-((trimethylsilyl) methyl)ethanamine (8.14 g, 50.5 mmol). Thebiphasic mixture was stirred at 0° C. for 3 hours, then K₂CO₃ (6.97 g,50.5 mmol) was added and the mixture was stirred at 0° C. for 1 hour.The yellow oil was decanted onto K₂CO₃ (2.00 g, 14.4 mmol), and themixture was stirred at ambient temperature for 2 hours. After the yellowoil was decanted, the solid K₂CO₃ was washed with Et₂O (2×10 mL), andthe Et₂O washings were combined with the decanted yellow oil andconcentrated on a rotary evaporator to yield the product as a yellow oil(9.92 g, 96% yield). ¹H NMR (CDCl₃) δ 4.00 (s, 2H), 3.37-3.43 (m, 2H),3.29 (s, 3H), 3.19 (s, 3H), 2.77-2.82 (m, 2H), 2.18 (s, 2H), 0.00 (s,9H).

Preparation D

(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochlorideStep A: Preparation of (R)-3-cinnamoyl-4-phenyloxazolidin-2-one

A THF (50 mL) solution of (R)-4-phenyloxazolidin-2-one (5.90 g, 36.2mmol) was cooled to −78° C. and treated with lithiumbis(trimethylsilyl)amide (36.9 mL, 36.9 mmol, 1.0 M in THF) dropwiseover 15 minutes. After 15-minute stirring at −78° C., a THF (10 mL)solution of cinnamoyl chloride (6.33 g, 38.0 mmol) was then introduced.The mixture was stirred for 1 hour at −78° C. and 2 hours at ambienttemperature before it was quenched with saturated NaHCO₃ (50 mL) andstirred for 1 hour. The mixture was diluted with EtOAc (200 mL), washedwith water and brine, dried over MgSO₄, filtered and concentrated togive the product as a pale yellow solid (10.6 g, 99.9% yield). MS (apci)m/z=293.9 (M+H).

Step B: Preparation of(R)-3-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidine-3-carbonyl)-4-phenyloxazolidin-2-one

A toluene (500 mL) solution of (R)-3-cinnamoyl-4-phenyloxazolidin-2-one(8.00 g, 27.3 mmol) and TFA (0.210 mL, 2.73 mmol) was first cooled to5-10° C., followed by dropwise addition of a toluene (30 mL) solution of2-methoxy-N-(methoxymethyl)-N-((trimethylsilyl)methyl)ethanamine(Preparation C, 8.40 g, 40.9 mmol). The resulting mixture was warmed upto ambient temperature and stirred for 3 hours, then washed withsaturated NaHCO₃ and water, dried with MgSO₄, filtered and concentratedin vacuo. The crude material was purified by silica columnchromatography, eluting with 16-20% EtOAc/hexanes, to afford the product(6.5 g, 60% yield). MS (apci) m/z=395.2 (M+H).

Step C: Preparation of(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidine-3-carboxylic acid

To a 1M aqueous solution of LiOH (41.2 mL, 41.2 mmol) at 0° C. was addedH₂O₂ (3.37 mL, 33.0 mmol, 30 wt %). The mixture was then added tosolution of(R)-3-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidine-3-carbonyl)-4-phenyloxazolidin-2-one(6.50 g, 16.5 mmol) in THF (100 mL) over 10 minutes at 0° C. After 1hour stirring, 2.0 M aqueous Na₂SO₃ (33.0 mL, 65.9 mmol) was introducedat 0° C. and the reaction mixture was warmed to ambient temperature.After stirring for 10 minutes, the mixture was washed with EtOAc (50mL). The aqueous layer was acidified with 1 N HCl until pH 3-5, thentreated with NaCl (10 g), then extracted with 10% iPrOH/DCM. The organiclayer was dried with MgSO₄, filtered and concentrated to give theproduct (4.11 g, 100% yield). MS (apci) m/z=250.1 (M+H).

Step D: Preparation of benzyl(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-ylcarbamate

To a solution of(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidine-3-carboxylic acid (4.11g, 16.5 mmol) in toluene (70 mL) was added TEA (5.74 mL, 41.2 mmol)followed by diphenyl phosphoryl azide (4.99 mL, 23.1 mmol). The mixturewas stirred at ambient temperature for 1 hour and then heated to refluxfor 1 hour. Benzyl alcohol (3.42 mL, 33.0 mmol) was then added and thereaction mixture was refluxed for 15 hours. The reaction mixture wastreated with EtOAc, washed with water, dried over MgSO₄, filtered andconcentrated in vacuo. The crude material was purified by silica columnchromatography, eluting with 1% MeOH/DCM to afford the product (2.5 g,43% yield). MS (apci) m/z=355.2 (M+H).

Step E: Preparation of(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride

Benzyl (3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-ylcarbamate(0.257 g, 0.725 mmol) and TFA (3.91 mL, 50.8 mmol) were heated at 60° C.for 17 hours. The reaction mixture was concentrated in vacuo, usingtoluene to azeotrope, then treated with 2 N HCl in Et₂O and concentratedagain to give the title compound (0.21 g, 100% yield) as an off-whitesolid. MS (apci) m/z=221.2 (M+H).

Preparation E

(3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminetrifluoroacetate Step A: Preparation of(R,E)-3-(3-(3,5-difluorophenyl)acryloyl)-4-phenyloxazolidin-2-one

To a solution of (E)-3-(3,5-difluorophenyl)acrylic acid (10.0 g, 54.3mmol) in Et₂O (150 mL) at 0° C. was added DIEA (9.48 mL, 54.3 mmol)followed by pivaloyl chloride (6.69 mL, 54.3 mmol). The mixture wasstirred at 0° C. for 1 hour and cooled to −78° C. Meanwhile(R)-4-phenyloxazolidin-2-one (8.86 g, 54.3 mmol) in THF (200 mL) wascooled to −78° C. and butyllithium (21.7 mL, 2.5 M, 54.3 mmol) was addedslowly. The mixture was stirred for 20 minutes at −78° C. andtransferred by cannula to the solution of mixed anhydride. The combinedmixture was stirred at −78° C. for 15 min, allowed to warm to 0° C. andstirred for an additional 30 minutes. The reaction mixture was quenchedwith saturated NH₄Cl (25 mL), diluted with EtOAc (600 mL), washed withwater, NaHCO₃, and brine, dried over MgSO₄, and concentrated in vacuo.The crude material was purified by silica column chromatography, elutingwith 10-20% Ethyl acetate/Hexanes to afford the product (11.0 g, 61.5%yield).

Step B: Preparation of(3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminetrifluoroacetic acid salt

Prepared by the methods described in Preparation D, Steps B through E,replacing (R)-3-cinnamoyl-4-phenyloxazolidin-2-one with(R,E)-3-(3-(3,5-difluorophenyl)acryloyl)-4-phenyloxazolidin-2-one toafford the title compound (1.70 g, 102% yield). MS (apci) m/z=257.2(M+H).

Preparation F

(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine

Prepared according to the method described in Preparation D, replacingcinnamoyl chloride with (E)-3-(3,4-difluorophenyl)acryloyl chloride. MS(apci) m/z=257.1 (M+H).

Preparation G

(3S,4R)-1-(2-methoxyethyl)-4-(3-(trifluoromethyl)phenyl)pyrrolidin-3-aminedihydrochloride Step A: Preparation of tert-butyl(3S,4R)-1-(2-methoxyethyl)-4-(3-(trifluoromethyl)-phenyl)pyrrolidin-3-ylcarbamate

A solution of tert-butyl(3S,4R)-4-(3-(trifluoromethyl)phenyl)-pyrrolidin-3-ylcarbamate (100 mg,0.303 mmol, commercially available), N,N-diethylpropan-2-amine (0.145mL, 0.908 mmol) and 1-bromo-2-methoxyethane (0.0361 mL, 0.363 mmol) inDMF (1 mL) was stirred at ambient temperature for 2 hours, then heatedto 60° C. for 4 hours, then cooled to ambient temperature overnight.After partitioning between EtOAc and saturated NaHCO₃ (10 mL each), theorganic layer was washed with water and brine (2×10 mL each), dried overNa₂SO₄, filtered and concentrated to yield the crude product as whitesolid (80 mg, 68% yield). LCMS (apci) m/z=389.1 (M+H).

Step B: Preparation of(3S,4R)-1-(2-methoxyethyl)-4-(3-(trifluoromethyl)phenyl)-pyrrolidin-3-aminedihydrochloride

A solution of tert-butyl(3S,4R)-1-(2-methoxyethyl)-4-(3-(trifluoromethyl)phenyl)pyrrolidin-3-ylcarbamate(80.0 mg, 0.206 mmol) in 5-6 N HCl in IPA (4.12 mL, 20.6 mmol) wasstirred at ambient temperature for 1 hour, followed by concentrating invacuo and triturating with Et₂O to afford the product as beige solid (74mg, 99.5% yield). LCMS (apci) m/z=289.1 (M+H).

Preparation H

(3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride

Prepared according to the method of Preparation G, replacing tert-butyl(3S,4R)-4-(3-(trifluoromethyl)phenyl)-pyrrolidin-3-ylcarbamate withtert-butyl (3S,4R)-4-(3-fluorophenyl) pyrrolidin-3-ylcarbamate to affordthe title compound. LCMS (apci) m/z=239.1 (M+H).

Preparation I

(3S,4R)-4-(2,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride

Prepared according to the method of Preparation G, replacing tert-butyl(3S,4R)-4-(3-(trifluoromethyl)phenyl)-pyrrolidin-3-ylcarbamate withtert-butyl (3S,4R)-4-(2,4 di-fluoro-phenyl)pyrrolidin-3-ylcarbamate toafford the title compound. LCMS (apci) m/z=257.1 (M+H).

Preparation J

(3S,4R)-4-(2, 5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride

Prepared according to the method of Preparation G, replacing tert-butyl(3S,4R)-4-(3-(trifluoromethyl)phenyl)-pyrrolidin-3-ylcarbamate withtert-butyl (3S,4R)-4-(2,5 di-fluoro-phenyl)pyrrolidin-3-ylcarbamate toafford the title compound. LCMS (apci) m/z=257.1 (M+H).

Preparation K

(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride

Prepared according to the method described in Preparation D, replacingcinnamoyl chloride with (E)-3-(4-fluorophenyl)acryloyl chloride. MS(apci) m/z=239.1 (M+H).

Preparation L1

(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine Step A:Preparation of (E)-1-fluoro-4-(2-nitrovinyl)benzene

Acetic acid (2.0 L, 35.5 mol) and ammonium acetate (310.5 g, 4.03 mol)were stirred at ambient temperature for 1 hour, then nitromethane (611mL, 11.3 mol) and 4-fluorobenzaldehyde (200 g, 1.61 mol) were added andthe reaction mixture was heated to 90° C. for 3 hours. The reaction wasallowed to cool to ambient temperature, then H₂O (4 L) was added over 2hours with mechanical stirring. The suspension was stirred 1 hour, thenfiltered and washed with 2:1 water/acetic acid (500 mL). The solids weredried in a vacuum oven (50° C.) to afford the title product as a paleyellow solid (238 g, 1.42 mol, 88% yield). ¹H NMR (CDCl₃) δ 7.98 (1H),7.55 (3H), 7.16 (2H).

Step B: Preparation oftrans-3-(4-fluorophenyl)-1-(2-methoxyethyl)-4-nitropyrrolidine

To a suspension of (E)-1-fluoro-4-(2-nitrovinyl)benzene (201 g, 1.20mol) in DCM (1.09 L) and TFA (9.3 mL, 120 mmol) was added dropwise over30 minutes2-methoxy-N-(methoxymethyl)-N-((trimethylsilyl)methyl)ethanamine(Preparation C; 383 g, 1.86 mol) and the internal reaction temperaturewas maintained between 23-36° C. by cooling in an ice bath. The reactionmixture was poured into aqueous phosphate buffer solution (pH 7, 500 mL)and diluted with DCM (300 mL). The phases were separated and the aqueousphase was extracted with DCM (400 mL). The organic phases were combined,washed with brine (300 mL), dried (MgSO₄), filtered and concentratedunder reduced pressure. The crude oil was purified by silica columnchromatography eluting with 40% EtOAc/heptane to afford the titlecompound as a yellow oil (245 g, 76% yield). MS (apci) m/z=269.1 (M+H).

Step C: Preparation oftrans-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine

To a solution oftrans-3-(4-fluorophenyl)-1-(2-methoxyethyl)-4-nitropyrrolidine (289 g,1.08 mol) in EtOH (1 L) was added platinum(IV) oxide (24.5 g, 108 mmol)in a Parr vessel and installed into a Parr shaker. The vessel wasevacuated and backfilled with nitrogen (3×), then evacuated andbackfilled with hydrogen (60 psi). The vessel was recharged withhydrogen as needed until the reaction was complete. The reaction mixturewas filtered through Celite® and rinsed with MeOH (50 mL), thenconcentrated under reduced pressure to afford the title compound as ayellow oil (243 g, 95% yield). MS (apci) m/z=239.1 (M+H).

Step D: Preparation of(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(2S,3S)-2,3-bis(4-methylbenzoyloxy)succinate

To a solution of(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (120 g,504 mmol) in THF (3.0 L) and H₂O (333 mL) was addeddi-p-toluoyl-D-tartaric acid (195 g, 504 mmol). Stirred at ambienttemperature for 1 hour, then placed in a freezer (−11° C.) for 18 hours.The mixture was stirred to give a slurry, filtered, and rinsed with Et₂O(4×100 mL). The solid was dried in vacuum oven (40° C.) for 4 hours,then recrystallized twice by the following procedure: the solid wasdissolved in THF (1.06 mL) and H₂O (118 mL) with heating to 45° C., thenallowing to cool to ambient temperature over 2 hours, then placed in afreezer (−11° C.) for 18 hours; the mixture was stirred to give aslurry, filtered, and rinsed with Et₂O (4×100 mL). After tworecrystallizations, the solid was dried in vacuum oven (40° C.) for 18hours to afford the title compound as a white crystalline solid (96 g,31% yield). MS (apci) m/z=239.2 (M+H).

Step E: Preparation of(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine

(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(2S,3S)-2,3-bis(4-methylbenzoyloxy)succinate (20 g, 32.0 mmol) wasdissolved in DCM (300 mL) and washed with 1M NaOH (2×200 mL). Thecombined aqueous phases were extracted with DCM (200 mL). The combinedorganic extracts were washed with brine (200 mL), dried (MgSO₄),filtered and concentrated, then dried under vacuum to afford the titlecompound as a yellow oil (6.17 g, 81%, >99% ee). MS (apci) m/z=239.1(M+H).

The following pyrrolidine intermediates were made according to themethod of Preparation L1, using the appropriate benzaldehyde in Step Aand replacing EtOH and platinum(IV) oxide with MeOH and Raney nickelrespectively in Step C. For preparation L3, the 90% THF/H₂O in Step Dwas replaced with 85% MeOH/H₂O.

Preparation # Structure Name Data L2

(3S,4R)-4-(3,5-difluorophenyl)- 1-(2-methoxyethyl)pyrrolidin- 3-amine MS(apci) m/z = 257.1 (M + H) L3

(3S,4R)-4-(3,4-difluorophenyl)- 1-(2-methoxyethyl)pyrrolidin- 3-amine(2S,3S)-2,3-bis(4- methylbenzoyloxy)succinate MS (apci) m/z = 257.1 (M +H) L4

trans-4-(3-chloro-4-fluoro- phenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine MS (apci) m/z = 273.1 (M + H) L5

trans-4-(4-chloro-3-fluoro- phenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine MS (apci) m/z = 273.1 (M + H) L6

trans-4-(3-chloro-5-fluoro- phenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine MS (apci) m/z = 273.1 (M + H) L7

trans-4-(3-chlorophenyl)-1-(2- methoxyethyl)pyrrolidin-3- amine MS(apci) m/z = 255.1 (M + H) L8

trans-4-(2,4-difluorophenyl)-1- (2-methoxyethyl)pyrrolidin-3- amine MS(apci) m/z = 256.1 (M + H) L9

tarns-4-(5-fluoropyridin-3-yl)- 1-(2-methoxyethyl)pyrrolidin- 3-amine MS(apci) m/z = 240.1 (M + H) L10

trans-4-(5-fluoropyridin-2-yl)- 1-(2-methoxyethyl)pyrrolidin- 3-amine ¹HNMR consistent with expected product L11

trans-4-(3-fluoropyridin-4-yl)- 1-(2-methoxyethyl)pyrrolidin- 3-amineNot available L12

trans-4-(5-chloropyridin-3-yl)- 1-(2-methoxyethyl)pyrrolidin- 3-amine MS(apci) m/z = 256.1 (M + H) L13

trans-1-(2-methoxyethyl)-4-(1- methyl-1H-pyrazol-4-yl)pyrrolidin-3-amine ¹H NMR consistent with expected product L14

trans-1-(2-methoxyethyl)-4- (1,2,3-thiadiazol-4- yl)pyrrolidin-3-amineNot available

Preparation L15

4-(trans-4-amino-1-(2-methoxyethyl)pyrrolidin-3-yl)benzonitrile

Prepared according to the method described in Preparation L1, Steps A toC, replacing 4-fluorobenzaldehyde with 4-formylbenzonitrile in Step Aand replacing EtOH and platinum(IV) oxide with MeOH, Zn (dust) andsaturated NH₄Cl, respectively in Step C. MS (apci) m/z=246.1 (M+H).

Preparation L16

3-(trans-4-amino-1-(2-methoxyethyl)pyrrolidin-3-yl)benzonitrile

Prepared according to the method described in Preparation L1, Steps A toC, replacing 4-fluorobenzaldehyde with 3-formylbenzonitrile in Step A,and replacing EtOH and platinum(IV) oxide with MeOH, Zn (dust) andsaturated NH₄Cl, respectively, in Step C. MS (apci) m/z=246.2 (M+H).

Preparation M

(3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-aminedihydrochloride

Prepared according to the method described in Preparation D, replacingcinnamoyl chloride with (E)-3-(3,4,5-trifluorophenyl)acryloyl chloride.¹H NMR (D₂O) δ 7.06-7.10 (m, 2H), 4.13-4.20 (m, 1H), 3.92-3.99 (m, 2H),3.71-3.74 (m, 1H), 3.57-3.63 (m, 3H), 3.41-3.49 (m, 3H), 3.25 (s, 3H).

Preparation N

Trans-5-(4-amino-1-(2-methoxyethyl)pyrrolidin-3-yl)-2-fluorobenzonitrileStep A: (E)-2-fluoro-5-(2-nitrovinyl)benzonitrile

To a solution of 2-fluoro-5-formylbenzonitrile (3.84 g, 25.0 mmol) in3:1 CH₃NO₂/CH₃CN (25 mL) was added DMAP (0.305 g, 2.50 mmol) and themixture stirred at ambient temperature for 23 hours. The mixture wascooled on an ice bath and Ac₂O (3.54 mL, 37.5 mmol) was added. Themixture was stirred for 5 minutes, allowed to reach ambient temperatureand stirred for 1 hour. The mixture was concentrated to a yellow solid.The solid was suspended in iPrOH (70 mL) and stirred for 10 minutes. Thesuspension was collected via vacuum filtration, the cake washed withiPrOH and dried in vacuum to afford the title compound as a light tanpowder (3.36 g, 70%). ¹H NMR (CDCl₃) δ 7.96 (d, 1H), 7.79-7.88 (m, 2H),7.57 (d, 1H), 7.36 (t, 1H).

Step B:Trans-2-fluoro-5-(1-(2-methoxyethyl)-4-nitropyrrolidin-3-yl)benzonitrile

Using (E)-2-fluoro-5-(2-nitrovinyl)benzonitrile in Step B of theprocedure describe in Preparation L1, the title compound was prepared aslight gold syrup (1.56 g, 53%). MS (apci) m/z=294.1 (M+H).

Step C:Trans-5-(4-amino-1-(2-methoxyethyl)pyrrolidin-3-yl)-2-fluorobenzonitrile

A solution oftrans-2-fluoro-5-(1-(2-methoxyethyl)-4-nitropyrrolidin-3-yl)benzonitrile(450 mg, 1.53 mmol) in MeOH (6.0 mL) was cooled to 0°. Zn dust (1.00 mg,15.3 mmol) and saturated aqueous NH₄Cl (1.0 mL) were added sequentiallyand the mixture was stirred for 5 minutes. The mixture was allowed toreach ambient temperature and stirred until complete by LCMS analysis.The mixture was filtered through packed Celite® using MeOH for rinsingand elution and the filtrate was concentrated to a colorless syrup. Thesyrup was treated with 1M K₂CO₃ (15 mL), mixed and extracted with CH₂Cl₂(3×). The combined CH₂Cl₂ extracts were dried over Na₂SO₄, filtered andconcentrated to provide the title compound as a colorless syrup (412 mg,100%). MS (apci) m/z=264.1 (M+H).

Preparation O

Trans-3-(4-amino-1-(2-methoxyethyl)pyrrolidin-3-yl)-5-fluorobenzonitrileStep A: 3-fluoro-5-formylbenzonitrile

A solution of 3-bromo-5-fluorobenzonitrile (5.00 g, 25.0 mmol) in dryTHF (25 mL) was cooled to 0° C. and 2M iPrMgCl (15.0 mL, 30.0 mmol) inTHF was added dropwise over 5 minutes. The mixture was stirred at 0° C.for 15 minutes then at ambient temperature for 1 hour. The mixture wascooled to 0° C. and dry DMF (5.81 mL, 75.0 mmol) was added. The mixturewas stirred for 17 hours during which time the temperature reachedambient temperature after 2 hours. The mixture was added to ice water(150 mL) and Et₂O (100 mL). The biphasic mixture was stirred and treatedwith 6M HCl to aqueous pH=3. The organic layer was removed and theaqueous layer extracted with Et₂O (2×). The combined Et₂O fractions werewashed with saturated NaCl and dried over MgSO₄/activated carbon. Thedried solution was filtered through a SiO₂ plug eluting with Et₂O. Thefiltrate was concentrated to give the title compound as a yellow solidthat was dried in vacuum (3.68 g, 99%). ¹H NMR (CDCl₃) δ 10.0 (s, 1H),8.00 (s, 1H), 7.81-7.86 (m, 1H), 7.62-7.67 (m, 1H).

Step B:Trans-3-(4-amino-1-(2-methoxyethyl)pyrrolidin-3-yl)-5-fluorobenzonitrile

The tile compound was prepared using 3-fluoro-5-formylbenzonitrile inthe procedure described for the preparation oftrans-5-(4-amino-1-(2-methoxyethyl)pyrrolidin-3-yl)-2-fluorobenzonitrile(Preparation N). The compound was isolated as a colorless syrup (542 mg,93%). MS (apci) m/z=264.1 (M+H).

Preparation P

Trans-1-(2-methoxyethyl)-4-(4-chlorophenyl)pyrrolidin-3-amine Step A:Trans-3-(4-chlorophenyl)-1-(2-methoxyethyl)-4-nitropyrrolidine

Using (E)-1-chloro-4-(2-nitrovinyl)benzene in Step B of the proceduredescribe in Preparation L1, the title compound was prepared as viscouscolorless oil (5.10 g, 64%). MS (apci) m/z=285.0 (M+H).

Step B: Trans-1-(2-methoxyethyl)-4-(4-chlorophenyl)pyrrolidin-3-amine

To a suspension of 2800 Raney Nickel (50 wt % in H₂O, 0.873 g, 5.10mmol) in MeOH (25 mL) was addedtrans-3-(4-chlorophenyl)-1-(2-methoxyethyl)-4-nitropyrrolidine (2.90 g,10.2 mmol) in MeOH (25 mL). The mixture was flushed with H₂ gas andstirred under a balloon atmosphere of H₂ for 16 hours. The mixture waspurged with N₂ gas and filtered through packed Celite® using MeOH forrinsing and elution. The filtrate was concentrated to a cloudy oil. Theoil was dissolved in CH₂Cl₂ and dried over Na₂SO₄/activated carbon. Thesolution was filtered and concentrated to provide the title compound asa light gold oil that was dried in vacuum (2.46 g, 95%). MS (apci)m/z=255.1 (M+H).

Table 1 provides a list of commercially available pyrazole intermediateswhich were used in the synthesis of compounds described in the Examples.

TABLE 1 Pyrazole Vendor/Catalog# CAS#

Oakwood, 021512 126208-61-5

Array BioPharma, A1075-0 N/A

Maybridge, GK03066 1192-21-8

J&W PharmaLab, 68-0257S N/A

Ryan Scientific, EN300-14400 89399-92-8

Oakwood, 021516 N/A

Alfa Aesar, AAB20095-06 118430-73-2

Aldrich, 532223 3524-32-1

Accela ChemBio Chem Co, SY003755 876299-97-7

ChemImpex, 18122 778611-16-8

Oakwood, 017105 175137-45-8

Alfa Aesar, AAB20464-06 5356-71-8

Aldrich, 541001 1131-18-6

Alfa Aesar, AAA15754-06 10199-50-5

TCI America, A0174 826-85-7

Oakwood, 023890 N/A

J&W Pharmalab, 68-0035S 1187931-80-1

VWR, EN300-09508 N/A

ChemBridge, 4019184 885529-68-0

ChemBridge, 4001950 N/A

ChemImpex, 19156 337533-96-7

ChemImpex, 19155 898537-77-4

ChemBridge, 4006072 N/A

Oakwood, 005982 5346-56-5

ChemImpex, 18771 182923-55-3

Maybridge, KM00278 118430-74-3

Maybridge, KM00835 118430-78-7

ChemBridge, 4015288 N/A

ChemBridge, 4015289 N/A

Matrix, 020274 N/A

Matrix, 019183 N/A

Maybridge, KM 04038 126417-82-1

ChemBridge, 4001950 N/A

Lancaster, AAA17470-06 7152-40-1

ChemBridge, 4010196 91642-97-6

VWR, AAA13296-14 16078-71-0 N/A = Not available

Intermediate P1

Ethyl 3-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)benzoate

To a suspension of ethyl 3-hydrazinylbenzoate hydrochloride (500 mg,2.31 mmol) in EtOH (20 mL) was added 4,4-dimethyl-3-oxopentanenitrile(318 mg, 2.54 mmol). The reaction mixture was heated to reflux for 18hours, then cooled to ambient temperature and concentrated in vacuo. Thecrude product was purified by silica column chromatography, eluting with0-5% MeOH/DCM to yield the product as a yellow oil (154 mg, 23% yield).MS (apci) m/z=288.2 (M+H).

The compounds in Table 2 were prepared by the method as described forIntermediate P1, substituting 4,4-dimethyl-3-oxopentanenitrile with theappropriate cyanoketone and ethyl 3-hydrazinylbenzoate hydrochloridewith the appropriate hydrazine.

TABLE 2 Intermediate # Structure Data P2 

MS (apci) m/z = 188.2 (M + H) P3 

MS (apci) m/z = 218.1 (M + H) P4 

MS (apci) m/z = 218.2 (M + H) P5 

MS (apci) m/z = 188.2 (M + H) P6 

MS (apci) m/z = 214.2 (M + H) P7 

MS (apci) m/z = 188.2 (M + H) P8 

MS (apci) m/z = 301.0 (M + H) P9 

MS (apci) m/z = 218.1 (M + H) P10

MS (apci) m/z = 175.2 (M + H) P11

MS (apci) m/z = 237.3 (M + H) P12

MS (apci) m/z = 188.2 (M + H) P13

MS (apci) m/z = 188.2 (M + H) P14

MS (apci) m/z = 188.2 (M + H) P15

MS (apci) m/z = 204.2 (M + H) P16

MS (apci) m/z = 204.2 (M + H) P17

MS (apci) m/z = 199.0 (M + H) P18

MS (apci) m/z = 199.1 (M + H) P19

MS (apci) m/z = 192.2 (M + H) P20

MS (apci) m/z = 192.2 (M + H) P21

MS (apci) m/z = 232.2 (M + H) P22

MS (apci) m/z = 204.2 (M + H) P23

MS (apci) m/z = 206.1 (M + H)

Intermediate P101

2-(1-methyl-1H-pyrazol-4-yl)-2,4,5,6-tetrahydrocyclopenta-[c]pyrazol-3-amineStep A: Preparation of di-tert-butyl1-(1-methyl-1H-pyrazol-4-yl)hydrazine-1,2-dicarboxylate

To a solution of 4-bromo-1-methyl-1H-pyrazole (1.93 mL, 18.6 mmol) inether (37.3 mL) cooled to −78° C. was added nBuLi (23.3 mL, 37.3 mmol).After stirring at −78° C. for 30 minutes, a solution of di-t-butylazodicarboxylate (4.29 g, 18.6 mmol) in Et₂O (37.3 mL, 18.6 mmol) wasadded dropwise. After 1 hour, the reaction mixture was warmed up to −20°C. and quenched with ice. After warming to ambient temperature, themixture was filtered and rinsed with Et₂O. The resulting solid was takenup in a mixture of DCM and water, and the mixture was phase separated.The organic layer was dried with MgSO₄, filtered and concentrated invacuo to afford the first batch of product as a white solid (1.64 g, 28%yield). A second batch of product was recovered from the filtrate bysilica column chromatography, eluting with 40-60% hexanes/EtOAc (0.51 g,8.8% yield). MS (apci) m/z=313.0 (M+H).

Step B: Preparation of2-(1-methyl-1H-pyrazol-4-yl)-2,4,5,6-tetrahydrocyclopenta-[c]pyrazol-3-amine

To a solution of di-tert-butyl1-(1-methyl-1H-pyrazol-4-yl)hydrazine-1,2-dicarboxylate (103 mg, 0.330mmol) in EtOH (1.65 mL, 0.330 mmol) was added concentrated HCl (137 μL,1.65 mmol). The mixture was stirred at ambient temperature for 5minutes, then cooled in an ice bath followed by addition of2-oxocyclopentanecarbonitrile (36.0 mg, 0.330 mmol). After stirring for5 minutes, the reaction mixture was warmed to ambient temperatureovernight. The reaction mixture was concentrated and partitioned inwater and DCM. After phase-separation, the aqueous layer was basified(pH 10) and then extracted with DCM (3×10 mL). The combined organicextracts were dried with MgSO₄, filtered and concentrated in vacuo. Thecrude material was purified by reverse-phase column chromatography,eluting with 0-100% acetonitrile/water to afford the product as a yellowsolid (4.5 mg, 6.7% yield). MS (apci) m/z=204.1 (M+H).

Intermediate P102

3-tert-butyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine Step A:Preparation of (tetrahydro-2H-pyran-4-yl)hydrazine hydrochloride

A suspension of dihydro-2H-pyran-4(3H)-one (2.00 g, 20.0 mmol) andtert-butyl hydrazinecarboxylate (2.64 g, 20.0 mmol) in hexanes (20.0 mL)was refluxed for 2 hours. After cooling, BH₃-THF complex (20.0 mL, 20.0mmol) was added and the reaction mixture was stirred for 1 hour. Themixture was then treated with 4 N HCl in dioxane (20.0 mL, 79.9 mmol),followed by 3 drops of water. After stirring at ambient temperature for1 hour, the reaction mixture was filtered and rinsed with EtOAc toafford the product as a solid (2.39 g, 78.4% yield). MS (apci) m/z=117.0(M+H).

Step B: Preparation of3-tert-butyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine

Prepared by the method as described in for the preparation ofIntermediate P1, substituting (tetrahydro-2H-pyran-4-yl)hydrazinedihydrochloride for ethyl 3-hydrazinylbenzoate hydrochloride to yieldthe product as a yellow oil (0.472 g, 99.9% yield). MS (apci) m/z=224.1(M+H).

Intermediate P103

2-(pyridin-2-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine Step A:Preparation of 2-(2-(pyridin-2-yl)hydrazono)cyclopentane-carbonitrile

A solution of 2-hydrazinylpyridine (0.200 g, 1.83 mmol) and2-oxocyclopentanecarbonitrile (0.200 g, 1.83 mmol) in MeOH (9.16 mL) wastreated with concentrated HCl (0.764 mL, 9.16 mmol) and refluxed for 16hours. The reaction mixture was concentrated in vacuo, and thenpartitioned in water and DCM. After phase-separation, the aqueous layerwas washed with DCM, basified (saturated NaHCO₃, pH 10), and extractedwith DCM. The combined organic layers were dried with MgSO₄, filteredand concentrated. The crude material was purified by silica columnchromatography, eluting with 100% EtOAc to afford the product (0.289 g,78.6% yield). MS (apci) m/z=201.2 (M+H).

Step B: Preparation of2-(pyridin-2-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine

A solution of 2-(2-(pyridin-2-yl)hydrazono)cyclopentanecarbonitrile(0.243 g, 1.21 mmol) in EtOH (6.06 mL, 1.21 mmol) was treated with 6 MHCl (0.202 mL, 1.21 mmol) and refluxed for 3 days. After removal of thesolvent, the crude residue was diluted in water, basified (saturatedNaHCO₃, pH 10) and extracted with DCM. The combined organic layers weredried with MgSO₄, filtered and concentrated. The crude material waspurified by silica column chromatography, eluting with 50% EtOAc/hexanesto afford the product (0.198 g, 81.6% yield). MS (apci) m/z=201.2 (M+H).

Intermediate P104

2-(pyridin-3-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine

Prepared by the method described above for Intermediate P103,substituting 3-hydrazinylpyridine for 2-hydrazinyl pyridine to affordthe title product. MS (apci) m/z=201.1 (M+H).

Intermediate P105

6,6-dimethyl-2-phenyl-2,4, 5,6-tetrahydrocyclopenta[c]pyrazol-3-amineStep A: Preparation of 5-chloro-2,2-dimethylpentanenitrile

Isobutyronitrile (1.38 g, 20.0 mmol) and 1-bromo-3-chloropropane (3.46g, 22.0 mmol) were sequentially added to a 1 M solution of lithiumbis(trimethylsilyl)amide (20.0 mL, 20.0 mmol) while stirring. Afterstirring at 70° C. for 16 hours, the reaction mixture was quenched withwater then extracted with DCM. The combined organic layers were driedwith MgSO₄, filtered and concentrated in vacuo to afford5-chloro-2,2-dimethylpentanenitrile (2.91 g, 100% yield). ¹H NMR (CDCl₃)δ 3.57-3.61 (m, 2H), 1.94-2.02 (m, 2H), 1.67-1.72 (m, 2H), 1.37 (s, 6H).

Step B: Preparation of 2,2-dimethylhexanedinitrile

A suspension of 5-chloro-2,2-dimethylpentanenitrile (2.91 g, 20.0 mmol)and NaCN (1.57 g, 32.0 mmol) in DMF (20.0 mL) and water (1 mL) washeated at 100° C. for 16 hours. After cooling, the reaction mixture wasdiluted with water and refluxed for 30 minutes, then cooled, poured intowater and stirred for 3 hours. The solution was then extracted withEt₂O. The combined Et₂O extracts were washed with H₂O, dried with MgSO₄,filtered and concentrated in vacuo to afford the product (2.20 g, 80.7%yield). ¹H NMR (CDCl₃) δ 2.42-2.47 (m, 2H), 1.83-1.92 (m, 2H), 1.67-1.72(m, 2H), 1.39 (s, 6H).

Step C: Preparation of 3,3-dimethyl-2-oxocyclopentanecarbonitrile

A suspension of KOtBu (0.511 g, 4.55 mmol) in toluene (18.4 mL) wastreated a toluene (2.0 mL) solution of 2,2-dimethylhexanedinitrile (1.00g, 7.34 mmol) and heated at 80° C. for 2 hours. The reaction mixture wasthen cooled to ambient temperature and quenched with water. The mixturewas separated and the organic layer was stirred in 2 N HCl (20 mL) for16 hours. The mixture was separated and the organic layer dried withMgSO₄, filtered and concentrated in vacuo to a yellow-white solid. Thecrude solid was purified by silica column chromatography, eluting with10-40% EtOAc/hexanes, to afford the product (0.250 g, 24.8% yield). ¹HNMR (CDCl₃) δ 3.20-3.26 (m, 1H), 2.38-2.47 (m, 1H), 2.14-2.25 (m, 1H),1.97-2.05 (m, 1H), 1.74-1.83 (m, 1H), 1.14 (s, 6H).

Step D: Preparation of6,6-dimethyl-2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine

Prepared by the method as described for Intermediate P1, substitutingphenylhydrazine for ethyl 3-hydrazinylbenzoate hydrochloride and3,3-dimethyl-2-oxocyclopentanecarbonitrile for4,4-dimethyl-3-oxopentanenitrile to afford the product (0.192 g, 46.2%yield) as a yellow solid. MS (apci) m/z=228.2 (M+H).

Intermediate P106

7,7-dimethyl-2-phenyl-4,5,6,7-tetrahydro-2H-indazol-3-amine Step A:Preparation of 2,2-dimethylheptanedinitrile

Prepared by the method as described for Intermediate P105, Steps A andB, substituting 1-bromo-4-chlorobutane for 1-bromo-3-chloropropane toyield the product (2.21 g, 73.7% yield). ¹H NMR (CDCl₃) δ 2.37-2.42 (m,2H), 1.53-1.77 (m, 6H), 1.36 (s, 6H).

Step B: Preparation of 3,3-dimethyl-2-oxocyclohexanecarbonitrile

A suspension of KOtBu (0.463 g, 4.13 mmol) in toluene (16.6 mL) wastreated with a solution of 2,2-dimethylheptanedinitrile (1.00 g, 6.66mmol) in toluene (2.0 mL) and heated at 80° C. for 48 hours. Aftercooling to ambient temperature, the reaction mixture was quenched withwater and phase-separated, and the organic layer was stirred with 2 NHCl (20 mL) for 16 hours. After phase-separation, the organic layer wasdried with MgSO₄, filtered and concentrated in vacuo. The crude materialwas purified by silica column chromatography, eluting with 10-20%EtOAc/hexanes to afford the product (0.374 g, 37.2% yield). ¹H NMR(CDCl₃) δ 3.72-3.78 (m, 1H), 2.42-2.50 (m. 1H), 1.78-2.04 (m, 4H),1.60-1.70 (m, 1H), 1.21 (s, 3H), 1.16 (s, 3H).

Step C: Preparation of7,7-dimethyl-2-phenyl-4,5,6,7-tetrahydro-2H-indazol-3-amine

Prepared by the method as described for Intermediate P1, substitutingphenylhydrazine for ethyl 3-hydrazinylbenzoate hydrochloride and3,3-dimethyl-2-oxocyclohexanecarbonitrile for4,4-dimethyl-3-oxopentanenitrile to yield the product as an off-whitesolid (0.490 g, 54.2% yield, 66% purity). MS (apci) m/z=242.2 (M+H).

Intermediate P107

3-isopropyl-4-methyl-1-phenyl-1H-pyrazol-5-amine Step A: Preparation of2,4-dimethyl-3-oxopentanenitrile

To a solution of propiononitrile (518 mg, 9.40 mmol) in THF (50 mL, 7.83mmol) at −78° C. under N₂ was slowly added lithiumbis(trimethylsilyl)amide (1M in THF) (7.83 mL, 7.83 mmol). After 30minutes, methyl isobutyrate (0.898 mL, 7.83 mmol) was added dropwise,and the reaction mixture was warmed to 0° C. A yellow precipitateformed, the reaction mixture was stirred for 1 hour, then diluted withH₂O (50 mL) to dissolve the solids. The mixture was extracted with Et₂O(25 mL), and the basic aqueous phase was acidified with 2M HCl (5 mL)and extracted with Et₂O (2×50 mL). The combined organic phases werewashed with brine (50 mL), dried with MgSO₄, filtered, and concentratedto afford the product (421 mg, 42.9% yield)

Step B: Preparation of 3-isopropyl-4-methyl-1-phenyl-1H-pyrazol-5-amine

Prepared by the method as described for Intermediate P1, substitutingphenyl hydrazine for ethyl 3-hydrazinylbenzoate hydrochloride and4,4-dimethyl-3-oxopentanenitrile with 2,4-dimethyl-3-oxopentanenitrileto yield the product as a yellow syrup (0.587 g, 81.1% yield). MS (apci)m/z=216.2 (M+H).

Intermediate P108

2-phenyl-4,6-dihydro-2H-furo[3,4-c]pyrazol-3-amine Step A: Preparationof 4-oxotetrahydrofuran-3-carbonitrile

To a suspension of KOtBu (996.6 mg, 8.881 mmol) in THF (640.4 mg, 8.881mmol) cooled to 0° C. was added dropwise methyl 2-hydroxyacetate (675.7μL, 8.881 mmol) and stirred for 10 minutes. The acrylonitrile (589.1 μL,8.881 mmol) was then added and the reaction stirred at ambienttemperature. After 3 hours, the reaction was diluted with H₂O (50 mL),then extracted with Et₂O (25 mL) to remove any starting ester. The basicaqueous phase was acidified with 2M HCl (5 mL), then extracted with Et₂O(2×50 mL). The combined organic phases were dried with MgSO₄, filtered,and concentrated to afford a light brown oil (446 mg, 45.2% yield). ¹HNMR (CDCl₃) δ 4.63 (t, 1H), 4.24 (t, 1H), 4.14 (d, 1H), 4.02 (d, 1H),3.57 (t, 1H).

Step B: Preparation of2-phenyl-4,6-dihydro-2H-furo[3,4-c]pyrazol-3-amine

Prepared by the method as described for Intermediate P1, substitutingphenyl hydrazine for ethyl 3-hydrazinylbenzoate hydrochloride and4,4-dimethyl-3-oxopentanenitrile with4-oxotetrahydrofuran-3-carbonitrile to yield the product as areddish-brown syrup (182 mg, 22.5% yield). MS (apci) m/z=202.1 (M+H).

Intermediate P109

3-(methoxymethyl)-1-phenyl-1H-pyrazol-5-amine Step A: Preparation of4-methoxy-3-oxobutanenitrile

To a solution of methyl 2-methoxyacetate (0.4753 mL, 4.803 mmol) in THF(20 mL, 4.803 mmol) at −78° C. under N₂ was added acetonitrile (0.3033mL, 5.763 mmol), followed by lithium bis(trimethylsilyl)amide (1M inTHF) (4.803 mL, 4.803 mmol). After stirring 1 hour, the reaction mixturewas warmed to 0° C. and stirred for 1 hour. The reaction mixture wasthen diluted with H₂O (25 mL), washed with Et₂O (25 mL), thenneutralized with 2 M HCl (1.5 mL). This was extracted with Et₂O (2×25mL) and the combined organic phases were washed with brine (25 mL),dried with MgSO₄, filtered, and concentrated to afford the product (169mg, 31.1% yield). ¹H NMR (CDCl₃) δ 4.09 (s, 2H), 3.66 (s, 2H), 3.46 (s,3H)

Step B: Preparation of 3-(methoxymethyl)-1-phenyl-1H-pyrazol-5-amine

Prepared by the method as described for Intermediate P1, substitutingphenyl hydrazine for ethyl 3-hydrazinylbenzoate hydrochloride and4,4-dimethyl-3-oxopentanenitrile with 4-methoxy-3-oxobutanenitrile toyield the product as a pale yellow residue (6.0 mg, 2.0% yield). MS(apci) m/z=204.0 (M+H).

Intermediate P110

3-(methoxymethyl)-4-methyl-1-phenyl-1H-pyrazol-5-amine

Prepared according to the method as described for Intermediate P109,replacing acetonitrile with propionitrile to afford the product as anorange residue. MS (apci) m/z=218.0 (M+H).

Intermediate P111

2-(5-amino-1-phenyl-1H-pyrazol-3-yl)-2-methylpropan-1-ol Step A:Preparation of methyl3-(tert-butyldimethylsilyloxy)-2,2-dimethylpropanoate

Methyl 3-hydroxy-2,2-dimethylpropanoate (1.000 g, 7.567 mmol), TBDMS-Cl(1.140 g, 7.567 mmol) and imidazole (0.5666 g, 8.323 mmol) weredissolved in DMF (5 mL, 7.567 mmol) and stirred at ambient temperatureovernight. The reaction mixture was diluted with H₂O (25 mL) andextracted with EtOAc (2×25 mL). The combined organic phases were washedwith brine (25 mL), dried with MgSO₄, filtered and concentrated toafford the product (1.92 g, 103% yield). ¹H NMR (CDCl₃) δ 3.66 (s, 3H),3.57 (s, 2H), 1.15 (s, 6H), 0.87 (s, 9H), 0.02 (s, 6H).

Step B: Preparation of5-(tert-butyldimethylsilyloxy)-4,4-dimethyl-3-oxopentanenitrile

Prepared according to the method described for Intermediate P109,replacing methyl 2-methoxyacetate with methyl3-(tert-butyldimethylsilyloxy)-2,2-dimethylpropanoate to afford theproduct as a pale yellow residue. ¹H NMR (CDCl₃) δ 3.70 (s, 2H), 3.55(s, 2H), 1.15 (s, 6H), 0.89 (s, 9H), 0.06 (s, 6H).

Step C: Preparation of2-(5-amino-1-phenyl-1H-pyrazol-3-yl)-2-methylpropan-1-ol

Prepared by the method as described for Intermediate P1, substitutingphenyl hydrazine for ethyl 3-hydrazinylbenzoate hydrochloride and4,4-dimethyl-3-oxopentanenitrile with methyl3-(tert-butyldimethylsilyloxy)-2,2-dimethylpropanoate to yield theproduct as yellow syrup (74 mg, 66% yield). MS (apci) m/z=232.2 (M+H).

Intermediate P112

2-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-2-methylpropan-1-ol

Prepared according to the method described for Intermediate P111,replacing acetonitrile with propionitrile to afford the product as ayellow residue. MS (apci) m/z=246.2 (M+H).

Intermediate P113

3-(3-methoxypropyl)-4-methyl-1-phenyl-1H-pyrazol-5-amine

Prepared according to the method described for Intermediate P109,replacing methyl 2-methoxyacetate with methyl 4-methoxybutanoate andreplacing acetonitrile with propionitrile in Step A to afford theproduct as an orange-brown syrup. MS (apci) m/z=246.1 (M+H).

Intermediate P114

1,1′-dimethyl-1H, 1′H-3,4′-bipyrazol-5-amine Step A: Preparation of3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropanenitrile

A solution of ethyl 1-methyl-1H-pyrazole-4-carboxylate (500 mg, 3.24mmol), toluene (7.50 mL, 70.4 mmol), and acetonitrile (346 μL, 6.49mmol) was treated in one portion with KOtBu (1092 mg, 9.73 mmol) to givea hazy solution. The reaction was allowed to stir at ambient temperaturefor one hour, and was determined to be complete by HPLC analysis. Themixture was treated with water (7.5 mL) and stirred for 1 minute, thenacidified with 3M HCl (3027 μL, 9.08 mmol) to pH 5.5-6. The aqueouslayer was extracted with ethyl acetate (3×5 mL) and the combined organicextracts were concentrated in vacuo to give a yellow viscous oil, whichcompletely solidified upon placing under high vacuum to afford theproduct (102 mg, 21.1% yield). ¹H NMR (CDCl₃) δ 8.02 (s, 1H), 7.94 (s,1H), 3.98 (s, 3H), 3.82 (s, 2H)

Step B: Preparation of 1,1′-dimethyl-1H, 1′H-3,4′-bipyrazol-5-amine

Prepared by the method as described for Intermediate P1, substitutingmethyl hydrazine for ethyl 3-hydrazinylbenzoate hydrochloride andreplacing 4,4-dimethyl-3-oxopentanenitrile with3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropanenitrile to yield the product asan ivory white solid (45 mg, 44.6% yield). MS (apci) m/z=178.1 (M+H).

Intermediate P115

4-chloro-1,3-diphenyl-1H-pyrazol-5-amine

To a solution of 1,3-diphenyl-1H-pyrazol-5-amine (Table 1; 0.100 g,0.425 mmol) in acetonitrile (2 mL) was added N-chlorosuccinimide (0.0568g, 0.425 mmol). The pale yellow solution was stirred at ambienttemperature for 3 hours, then concentrated in vacuo and purified bysilica column chromatography eluting with 20% EtOAc/Hexanes to affordthe product as a light brown oil (0.10 g, 87% yield). MS (apci)m/z=270.0 (M+H).

Intermediate P116

4-bromo-1,3-diphenyl-1H-pyrazol-5-amine

Prepared according to the procedure described for Intermediate P115,substituting N-chloro succinimide with N-bromo-succinimide. MS (apci)m/z=313.9 (M+H).

Intermediate P117

4-chloro-3-methyl-1-phenyl-1H-pyrazol-5-amine

Prepared according to the procedure described for Intermediate P115,substituting 1,3-diphenyl-1H-pyrazol-5-amine with3-methyl-1-phenyl-1H-pyrazol-5-amine. MS (apci) m/z=207.9 (M+H).

Intermediate P118

4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-amine

Prepared according to the procedure described for Intermediate P117,substituting N-chloro succinimide with N-bromo-succinimide. MS (apci)m/z=251.9 (M+H).

Intermediate P119

4-chloro-1-methyl-3-phenyl-1H-pyrazol-5-amine

Prepared according to the procedure described for Intermediate P115,substituting 1,3-diphenyl-1H-pyrazol-5-amine with1-methyl-3-phenyl-1H-pyrazol-5-amine (Table 1). MS (apci) m/z=208.0(M+H).

Intermediate P120

4-bromo-1-methyl-3-phenyl-1H-pyrazol-5-amine

Prepared according to the procedure described for Intermediate P119,substituting N-chloro succinimide with N-bromo-succinimide. MS (apci)m/z=251.9 (M+H).

Intermediate P121

1-methyl-3-(4-(methylthio)phenyl)-1H-pyrazol-5-amine Step A: Preparationof 3-(4-(methylthio)phenyl)-3-oxopropanenitrile

To a suspension of NaH (60% in mineral oil) (154 mg, 3.84 mmol) indioxane (25.0 mL, 2.74 mmol) was added acetonitrile (0.217 mL, 4.12mmol). The reaction mixture was stirred at ambient temperature for 30minutes, then treated with methyl 4-(methylthio)benzoate (500 mg, 2.74mmol) and heated to reflux for 15 hours. The suspension was cooled, thendiluted with water (25 mL) and washed with Et₂O (25 mL). The aqueouslayer was neutralized with 2M HCl (1.8 mL) and extracted with Et₂O (2×25mL). The combined organic phases were washed with brine (25 mL), driedwith MgSO₄, filtered and concentrated in vacuo. The resultant residuewas purified by silica column chromatography eluting with 0-5% MeOH/DCMto afford the product (317 mg, 60.4% yield). ¹H NMR (CDCl₃) δ 7.82 (d,2H), 7.30 (d, 2H), 4.02 (s, 2H), 2.54 (s, 3H).

Step B: Preparation of1-methyl-3-(4-(methylthio)phenyl)-1H-pyrazol-5-amine

Prepared by the method as described in Intermediate P1, substitutingmethylhydrazine for ethyl 3-hydrazinylbenzoate hydrochloride andsubstituting 3-(4-(methylthio)phenyl)-3-oxopropanenitrile for4,4-dimethyl-3-oxopentanenitrile to yield the product as a yellow solid(0.307 g, 96.7% yield). MS (apci) m/z=220.0 (M+H).

Intermediate P122

2-(5-amino-1-phenyl-1H-pyrazol-3-yl)-2-methylpropanenitrile

Prepared according to the procedure for Intermediate P121, substitutingmethyl 4-(methylthio)benzoate with ethyl 2-cyano-2-methylpropanoate inStep A and phenyl hydrazine hydrochloride for methyl hydrazine in StepB. MS (apci) m/z=227.1 (M+H).

Intermediate P123

3-(4-(2-methoxyethoxy)phenyl)-1-methyl-1H-pyrazol-5-amine Step A:Preparation of 3-(4-(benzyloxy)phenyl)-3-oxopropanenitrile

Prepared according to the procedure described for Intermediate P121,substituting methyl 4-(methylthio)benzoate with methyl4-(benzyloxy)benzoate in Step A. ¹H NMR (CDCl₃) δ 7.90 (d, 2H), 7.42 (m,4H), 7.37 (m, 1H), 7.05 (d, 2H), 5.16 (s, 2H), 4.00 (s, 2H).

Step B: Preparation of3-(4-(benzyloxy)phenyl)-1-methyl-1H-pyrazol-5-amine

Prepared by the method as described for Intermediate P1, substitutingmethylhydrazine for ethyl 3-hydrazinylbenzoate hydrochloride and3-(4-(benzyloxy)phenyl)-3-oxopropanenitrile for4,4-dimethyl-3-oxopentanenitrile to yield the product as a yellow solid.MS (apci) m/z=280.1 (M+H).

Step C: Preparation of 4-(5-amino-1-methyl-1H-pyrazol-3-yl)phenol

To a solution of 3-(4-(benzyloxy)phenyl)-1-methyl-1H-pyrazol-5-amine (47mg, 0.17 mmol) in EtOH (5.0 mL) was added 5% Pd/C (9.0 mg, 0.0084 mmol)and stirred under a H₂ balloon for 17 hours. The reaction mixture wasfiltered through Celite®, rinsed with EtOH and concentrated in vacuo toafford the product (28 mg, 88% yield). MS (apci) m/z=190.1 (M+H).

Step D: Preparation of3-(4-(2-methoxyethoxy)phenyl)-1-methyl-1H-pyrazol-5-amine

To a solution of 4-(5-amino-1-methyl-1H-pyrazol-3-yl)phenol (14 mg,0.074 mmol) in DMSO (0.50 mL, 7.0 mmol) was added Cs₂CO₃ (48 mg, 0.15mmol) and 1-bromo-2-methoxyethane (9.7 μL, 0.10 mmol). The reactionmixture was stirred for 16 hours, then diluted with water (10 mL) andextracted with DCM (3×10 mL). The combined organic extracts were washedwith brine (10 mL), dried with MgSO₄, filtered and concentrated toafford the crude product (22 mg, 120% yield). The crude product was usedwithout purification in subsequent steps. MS (apci) m/z=248.0 (M+H).

Intermediate P124

1′-methyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-amine

Prepared according to the procedure described for Intermediate P114,substituting methylhydrazine with phenylhydrazine in Step B. MS (apci)m/z=240.0 (M+H).

Intermediate P125

4-methoxy-3-methyl-1-phenyl-1H-pyrazol-5-amine

Prepared according to the procedure for Intermediate P121, substitutingmethyl 4-(methylthio)benzoate with ethyl acetate and substitutingacetonitrile with 2-methoxyacetonitrile in Step A and phenyl hydrazinehydrochloride for methyl hydrazine in Step B. MS (apci) m/z=204.0 (M+H).

Intermediate P126

(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)methanol

Prepared according to the procedure for Intermediate P112, substitutingmethyl 3-hydroxy-2,2-dimethylpropanoate with ethyl 2-hydroxyacetate inStep A. MS (apci) m/z=204.1 (M+H).

Intermediate P127

2-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)ethanol

Prepared according to the procedure for Intermediate P112, substitutingmethyl 3-hydroxy-2,2-dimethylpropanoate with methyl 3-hydroxypropanoatein Step A. MS (apci) m/z=218.0 (M+H).

Intermediate P128

3-(2-methoxyethyl)-4-methyl-1-phenyl-1H-pyrazol-5-amine Step A:Preparation of 5-methoxy-2-methyl-3-oxopentanenitrile

To a suspension of NaNH₂ (50 wt % suspension in toluene) (330 mg, 4.23mmol) in THF (25 mL, 4.23 mmol) under N₂ at −78° C. was addedpropiononitrile (0.448 mL, 6.35 mmol), and the reaction mixture wasstirred for 30 minutes. Methyl 3-methoxypropanoate (0.495 mL, 4.23 mmol)was added and the reaction mixture was stirred at −78° C. for 1 hour,then at 0° C. for 2.5 hours. The reaction mixture was diluted with H₂O(25 mL) and washed with Et₂O (25 mL). The basic aqueous phase wasneutralized with 2M HCl (1.6 mL), then extracted with Et₂O (3×25 mL).The combined organic phases were washed with brine (25 mL), dried withMgSO₄, filtered, and concentrated to afford the crude product as a palegreenish oil (171 mg). The crude mixture was taken directly to the nextstep.

Step B: Preparation of3-(2-methoxyethyl)-4-methyl-1-phenyl-1H-pyrazol-5-amine

Prepared by the method as described for Intermediate P1, substituting5-methoxy-2-methyl-3-oxopentanenitrile for4,4-dimethyl-3-oxopentanenitrile and substituting phenylhydrazinehydrochloride for ethyl 3-hydrazinylbenzoate hydrochloride to yield theproduct as a yellow solid (56 mg, 20% yield). MS (apci) m/z=232.0 (M+H).

Intermediate P129

Phenyl(5-oxido-2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)carbamate

A THF (4 mL) solution of phenyl2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-ylcarbamate (IntermediateP130, Step B; 50 mg, 0.15 mmol) was cooled to −50° C. with an externaldry-ice/MeCN bath and treated with a THF (2 mL) solution of3-chlorobenzoperoxoic acid (33 mg, 0.13 mmol). After stirring for 1hour, the mixture was quenched with Na₂S₂O₃ and water, extracted withEtOAc, washed with NaHCO₃ and brine, dried with MgSO₄, filtered, andconcentrated to give the product which was directly used in next stepwithout further purification. MS (apci) m/z=354.1 (M+H).

Intermediate P130

Phenyl(5,5-dioxido-2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)carbamateStep A: Preparation of2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-amine

A suspension of 4-oxotetrahydrothiophene-3-carbonitrile (1.00 g, 7.86mmol) and phenylhydrazine hydrochloride (1.25 g, 8.65 mmol) in absoluteEtOH (40 mL) was refluxed for 2 hours. After removal of solvent underreduced pressure, the white solid residue was triturated with 1 N NaOH(40 mL). The solid was collected by filtration, washed with 0.1 N NaOH,water, and hexanes (approx. 10 mL each) then dried on high vacuum toyield the product as white solid (1.6 g, 95% yield). MS (apci pos)m/z=218.1 (M+H).

Step B: Preparation of phenyl2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-ylcarbamate

To a suspension of 2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-amine(500 mg, 2.30 mmol) in EtOAc (10 mL) was added NaOH (2M aq, 2.3 mL, 4.60mmol), followed by dropwise addition of phenyl carbonochloridate (0.400mL, 3.22 mmol). After stirring at ambient temperature for 2 hours,another portion of phenyl carbonochloridate (0.16 mL, 1.3 mmol) wasadded dropwise, and the reaction was stirred at ambient temperature for15 hours. The reaction mixture was diluted with EtOAc (20 mL) andphase-separated. The organic phase was washed with H₂O, brine (25 mLeach), then dried with Na₂SO₄, filtered and concentrated. The crudematerial was purified by reverse-phase column chromatography, elutingwith 5-70% acetonitrile/water to yield the product as white solid (0.5g, 64% yield). MS (apci pos) m/z=338.1 (M+H).

Step C: Preparation of phenyl(5,5-dioxido-2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)carbamate

To a turbid solution of phenyl2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-ylcarbamate (50 mg, 0.15mmol) in DCM (1.5 mL) at 0° C. was added MCPBA (91 mg, 0.37 mmol, 70-75%water complex), and the mixture was stirred at ambient temperature for10 min. The mixture was then diluted with DCM (3 mL) and washed withsaturated aqueous NaHCO₃ (3×2 mL) and saturated aqueous Na₂S₂O₃ (3×2mL). The organic layer was dried with MgSO₄, filtered and concentratedunder reduced pressure to yield the title product as light yellowishfoamy solid (31 mg, 57% yield, 95% pure). MS (apci pos) m/z=371.0 (M+H).

Intermediate P131

3-(imidazo[1,2-a]pyridin-5-yl)-1-methyl-1H-pyrazol-5-amine Step A:Methyl imidazo[1,2-a]pyridine-5-carboxylate

To a suspension of methyl 6-aminopicolinate (1.52 g, 10.0 mmol) in iPrOH(10 mL) was added 2-chloroacetaldehyde (2.57 mL, 20.0 mmol) and themixture was stirred at ambient temperature for 30 minutes. The resultingsolution was heated at 70° C. for 16 hours, then cooled to ambienttemperature and concentrated in vacuo. The residue was diluted with H₂O(40 mL) and treated with 1M K₂CO₃ until pH=10. The mixture was extractedwith EtOAc (3×) and the combined extracts were washed with saturatedNaCl and dried over MgSO₄/activated carbon. The dried solution waseluted through a SiO₂ plug capped with MgSO₄ layer using EtOAc forelution. The solution was concentrated to provide the title compound asa cream-white solid (1.73 g, 98.2% yield). MS (apci) m/z=177.0 (M+H).

Step B: 3-(imidazo[1,2-a]pyridin-5-yl)-3-oxopropanenitrile

A 1M solution of LiHMDS (3.15 mL, 3.15 mmol) in dry THF was cooled to−78° C. and acetonitrile (0.172 mL, 3.30 mmol) was added dropwise over 1minute. The mixture was stirred at −78° C. for 1 hour and a solution ofmethyl imidazo[1,2-a]pyridine-5-carboxylate (0.529 g, 3.00 mmol) in dryTHF (2.0 mL) was added. The mixture was allowed to reach ambienttemperature and was stirred for 2.5 hours. The mixture was poured intochilled H₂O (30 mL) and the resulting aqueous solution was extractedwith Et₂O (3×). The aqueous portion was cooled to 0° C. and 6M HCl wasadded slowly until pH=6. The resulting yellow suspension was filteredand the collected solid was washed with H₂O and EtOAc. The solid wasdried in vacuum to provide the title compound as a yellow solid (317 mg,57.1% yield). MS (apci) m/z=186.0 (M+H).

Step C: 3-(imidazo[1,2-a]pyridin-5-yl)-1-methyl-1H-pyrazol-5-amine

To a fine suspension of3-(imidazo[1,2-a]pyridin-5-yl)-3-oxopropanenitrile (229 mg, 1.24 mmol)in absolute EtOH (4 mL) was added methylhydrazine (78.1 μL, 1.45 mmol)and the resulting solution was stirred at ambient temperature for 2hours. The reaction mixture was heated at reflux for 5 hours andadditional methylhydrazine (200 μL) was added. The mixture was heated atreflux for 15 hours, cooled to ambient temperature and concentrated. Theresidual tan solid was dissolved in 5% MeOH/CH₂Cl₂ and eluted through aSiO₂ plug eluting with 5% MeOH/CH₂Cl₂. The eluent was concentrated andthe residual yellow solid was washed with MTBE and dried in vacuum toafford the title compound as a light yellow powder (150 mg, 56.9%yield). MS (apci) m/z=214.0 (M+H).

Intermediate P132

1-methyl-3-(pyrazin-2-yl)-1H-pyrazol-5-amine Step A: Preparation of3-oxo-3-(pyrazin-2-yl)propanenitrile

To a suspension of NaH (60% in mineral oil, 81.1 mg, 2.03 mmol) indioxane (15 mL) was added acetonitrile (0.114 mL, 2.17 mmol), followedby methyl pyrazine-2-carboxylate (200 mg, 1.45 mmol) and the reactionheated to reflux for 2.5 hours. The reaction mixture was cooled toambient temperature and diluted with H₂O (25 mL) and extracted with Et₂O(25 mL). The aqueous phase was neutralized with 2M aqueous HCl (0.7 mL),then extracted with 10% MeOH/DCM (3×25 mL). The combined organic phaseswere washed with brine (25 mL), dried with MgSO₄, filtered, andconcentrated to yield the crude product as an orange syrup (134 mg,62.9% yield). ¹H NMR (CDCl₃) δ 9.32 (d, 1H), 8.87 (d, 1H), 8.68 (dd,1H), 4.34 (s, 2H).

Step B: Preparation of 1-methyl-3-(pyrazin-2-yl)-1H-pyrazol-5-amine

To a suspension of 3-oxo-3-(pyrazin-2-yl)propanenitrile (67.0 mg, 0.455mmol) in EtOH (5 mL) was added methylhydrazine (0.024 mL, 0.455 mmol).The reaction mixture was refluxed for 15 hours, then concentrated invacuo. The crude product was purified by silica column chromatography,eluting with 0-5% MeOH/DCM to yield the product as a brown residue (33mg, 41% yield). MS (apci) m/z=176.2 (M+H).

Intermediate P133

1-methyl-3-(5-methylpyrazin-2-yl)-1H-pyrazol-5-amine

Prepared by the method as described for Intermediate P107, substitutingmethyl isobutyrate in Step A with methyl 5-methylpyrazine-2-carboxylateand propionitrile with acetonitrile to afford3-(5-methylpyrazin-2-yl)-3-oxopropanenitrile. In Step B, phenylhydrazinewas replaced by methylhydrazine to afford the title pyrazole. MS (apci)m/z=190.2 (M+H).

Intermediate P134

1,4-dimethyl-3-(5-methylpyrazin-2-yl)-1H-pyrazol-5-amine

Prepared by the method as described for Intermediate P107, substitutingmethyl isobutyrate in Step A with methyl 5-methylpyrazine-2-carboxylateto afford 2-methyl-3-(5-methylpyrazin-2-yl)-3-oxopropanenitrile. In StepB, phenylhydrazine was replaced by methylhydrazine to afford the titlecompound. MS (apci) m/z=204.1 (M+H).

Intermediate P135

3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-amine Step A: Preparation of5-amino-4-methyl-1-phenyl-1H-pyrazol-3 (2H)-one

A mixture of ethyl 2-cyanopropanoate (5.0 g, 46 mmol) andphenylhydrazine (5.9 g, 46 mmol) in dioxane (10 mL) was heated at 110°C. for 17 hours. The crude material was cooled to ambient temperature,concentrated, and triturated with cold EtOH and Et₂O. The resultantsolid was filtered, washed with Et₂O, and dried under vacuum to give theproduct as a white solid (3.4 g, 39% yield). MS (apci) m/z=190.0 (M−H).

Step B: Preparation of 3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-amine

To a suspension of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (10.0g, 52.9 mmol) in DMF (100 mL) was added K₂CO₃ (14.6 g, 106 mmol) andbromoethane (4.34 mL, 58.1) at ambient temperature. After stirring for17 hours, the reaction mixture was treated with EtOAc and washed withwater (3×, to obtain the N-alkylation product) and brine, dried withMgSO₄, filtered, and concentrated to give the product (5.35 g, 47%yield). MS (apci) m/z=218.1 (M+H).

The compounds in Table 3 were prepared by the method as described forIntermediate P135, substituting bromoethane with the appropriate alkylhalide or alkyl methanesulfonate.

TABLE 3 Intermediate # Structure Data P200

MS (apci) m/z = 248.1 (M + H) P201

MS (apci) m/z = 204.1 (M + H) P202

MS (apci) m/z = 229.0 (M + H) P203

MS (apci) m/z = 348.1 (M + H) P204

MS (apci) m/z = 310.0 (M + H) P205

MS (apci) m/z = 236.1 (M + H) P206

MS (apci) m/z = 264.0 (M + H) P207

MS (apci) m/z = 260.1 (M + H) P208

MS (apci) m/z = 274.1 (M + H) P209

MS (apci) m/z = 304.1 (M + H) P210

MS (apci) m/z = 262.1 (M + H) P211

MS (apci) m/z = 362.0 (M + H) P212

MS (apci) m/z = 304.1 (M + H)

Intermediate P136

3-(benzyloxy)-1-methyl-1H-pyrazol-5-amine Step A: Preparation of5-amino-1-methyl-4-phenyl-1H-pyrazol-3(2H)-one

To a suspension of ethyl 2-cyano-2-phenylacetate (2.56 g, 13.3 mmol) inEtOH (10 mL) was added dropwise methylhydrazine (1.09 mL, 19.9 mmol).The reaction was heated at 85° C. for 15 hours. The reaction mixture wascooled to 0° C. and filtered. The resultant solid was washed with coldEtOH (20 mL) and Et₂O (20 mL) to give the desired product (2.10 g, 83.7%yield). MS (apci) m/z=190.2 (M+H)

Step B: Preparation of 3-(benzyloxy)-1-methyl-1H-pyrazol-5-amine

A suspension of 5-amino-1-methyl-1H-pyrazol-3(2H)-one (0.35 g, 3.1mmol), Benzyl chloride (0.43 g, 3.4 mmol), and K₂CO₃ (1.3 g, 9.3 mmol)in DMF (4 mL) was heated at 70° C. for 17 hours. After cooling, thereaction mixture was treated with EtOAc, washed with water and brine,dried with MgSO₄, and concentrated in vacuo. The crude product waspurified by silica column chromatography eluting with 2-6% MeOH/DCM toafford the title compound (0.16 g, 25% yield). MS (apci) m/z=204.0(M+H).

Intermediate P137

3-methoxy-1-methyl-4-phenyl-1H-pyrazol-5-amine

To a suspension of 5-amino-1-methyl-4-phenyl-1H-pyrazol-3(2H)-one (StepA of the preparation of Intermediate P136; 208 mg, 1.10 mmol) and K₂CO₃(456 mg, 3.30 mmol) in DMF (5 mL) was added dropwise iodomethane (172mg, 1.21 mmol). The reaction mixture was stirred for 15 hours. Thesolvent was removed under reduced pressure and the residue was purifiedby silica column chromatography eluting with 33% EtOAc/Hexanes to givethe title pyrazole (66.0 mg, 30.4% yield). MS (apci) m/z=204.1 (M+H).

Intermediate P138

3-ethoxy-1-methyl-4-phenyl-1H-pyrazol-5-amine

Prepared as described in Intermediate P137, replacing iodomethane withiodoethane in Step B to afford the title compound. MS (apci) m/z=218.2(M+H).

Intermediate P139

3-ethoxy-1-phenyl-1H-pyrazol-5-amine

Prepared according to the procedure described for Intermediate 135,substituting ethyl-2-cyanopropanoate with ethyl-2-cyanoacetate in StepA. MS (apci) m/z=204.0 (M+H).

The compounds in the following Table were prepared by the method asdescribed for Intermediate P135, substituting bromoethane with theappropriate alkyl halide, alkyl methanesulfonate or epoxide.

Intermediate # Structure MS (apci) m/z P140

286.1 (M + H) P141

303.1 (M + H) P142

262.1 (M + H) P143

402.2 (M + H) P144

276.1 (M + H) P145

363.1 (M + H) P146

248.1 (M + H) P147

248.1 (M + H) P148

302.1 (M + H) P149

302.1 (M + H) P150

262.1 (M + H)

Intermediate 151

1′-(2-methoxyethyl)-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-amine Step A:Preparation of methyl 1-methyl-1H-1,2,4-triazole-3-carboxylate

To a stirred suspension of NaH (60% oil dispersion, 0.346 g, 8.66 mmol)in DMF (20 mL) was added dropwise a solution of methyl1H-1,2,4-triazole-3-carboxylate (1.00 g, 7.87 mmol) in DMF (20 mL) at 0°C. under nitrogen. The reaction mixture was stirred at 0° C. for 1 hour.MeI (0.982 mL, 15.7 mmol) was added dropwise. The reaction mixture wasstirred at ambient temperature overnight. The reaction was poured intocold water and extracted with EtOAc. The combined organic layers werewashed with brine, dried and concentrated. The residue was purified bycolumn chromatography (3:1 hexanes/EtOAc) to give the title compound(0.380 g, 34% yield) as a white solid. MS (apci) m/z=142.1 (M+H).

Step B: Preparation of 1′-(2-methoxyethyl)-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-amine

Prepared according to the method described for Intermediate P109, usingmethyl 1-methyl-1H-1,2,4-triazole-3-carboxylate as a replacement formethyl 2-methoxyacetate, and substituting propionitrile for acetonitrilein Step A. MS (apci) m/z=255.1 (M+H).

Intermediate 152

1′-(2-methoxyethyl)-4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-amine

Prepared according to the method described for Intermediate P109, usingethyl 1-(2-methoxyethyl)-1H-pyrazole-4-carboxylate as a replacement formethyl 2-methoxyacetate, and substituting propionitrile for acetonitrilein Step A.

Intermediate 153

5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carbonitrile

To a stirred solution of aniline (2.02 g, 21.7 mmol) in 6 N HCl (22 mL)was added dropwise a solution of NaNO₂ (1.50 g, 21.7 mmol) in water (20mL) at 0-5° C. The reaction mixture was stirred at 0° C. for 15 minutes.Acetic acid (10 mL) was added. This solution was added dropwise to astirred solution of ethyl 2,3-dicyanobutanoate (Prepared according tothe procedure described in Bioorganic & Medicinal Chemistry, 2004, 12,3345-3356, 3.60 g, 21.7 mmol) in acetic acid (12 mL) and water (18 mL)at 0° C. After stirring for 1 hour, concentrated ammonium hydroxide (50mL) was added dropwise followed by THF (50 mL). The reaction was stirredat ambient temperature overnight. The organic layer was separated. Theaqueous layer was extracted with EtOAc. The combined organic layers werewashed with brine, dried and concentrated. The residue was purified byflash chromatography on silica gel (3:1 hexanes/EtOAc) to give the titlecompound (2.95 g, 69% yield). MS (apci) m/z=198.9 (M+H).

Intermediate 154

2-(5-amino-4-methyl-1-phenyl-1H,1′H-3,4′-bipyrazol-1′-yl)ethanol Step A:Preparation of ethyl1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-4-carboxylate

Prepared according to the method described for Example 556, replacing1-bromo-2-methoxyethane with (2-bromoethoxy)(tert-butyl)dimethylsilanein Step A. MS (apci) m/z=298.9 (M+H).

Step B: Preparation of2-(5-amino-4-methyl-1-phenyl-1H,1′H-3,4′-bipyrazol-1′-yl)ethanol

Prepared according to the method described for Intermediate P109 usingethyl1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-4-carboxylate as areplacement for methyl 2-methoxyacetate, and substituting propionitrilefor acetonitrile in Step A. MS (apci) m/z=283.9 (M+H).

Intermediate 155

4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)-1-phenyl-1H-pyrazol-5-amineStep A: Preparation of ethyl 2-methyl-2H-1,2,3-triazole-4-carboxylate

A mixture of ethyl 2H-1,2,3-triazole-4-carboxylate (2.00 g, 14.2 mmol),K₂CO₃ (3.53 g, 25.5 mmol) and methyl iodide (3.54 mL, 56.7 mmol) inacetonitrile (40 mL) was stirred at 50° C. under nitrogen overnight.After cooling to ambient temperature, the mixture was filtered throughCelite®. The filtrate was concentrated in vacuo. The residue waspurified by flash chromatography on silica gel (4:1 hexane/EtOAc) togive the title compound (0.780 g, 35% yield). MS (apci) m/z=156.0 (M+H).

Step B: Preparation of4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)-1-phenyl-1H-pyrazol-5-amine

Prepared according to the method described for Intermediate P109 usingethyl 2-methyl-2H-1,2,3-triazole-4-carboxylate as a replacement formethyl 2-methoxyacetate, and substituting propionitrile for acetonitrilein Step A. MS (apci) m/z=254.9 (M+H).

Intermediate 156

3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-amine

To a stirred solution of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one(Intermediate P135, Step A, 1.00 g, 5.29 mmol) in MeCN (20 mL) was addedPOBr₃ (2.27 g, 7.93 mmol). The reaction mixture was heated at reflux for3 hours. The reaction was concentrate in vacuo. The residue was taken upin DCM. Saturated aqueous NaHCO₃ solution was carefully added. Theaqueous layer was extracted with DCM. The combined organic layers werewashed with brine, dried and concentrated. The residue was purified byflash chromatography on silica gel (1:2 hexane/EtOAc to give the titlecompound (0.23 g, 17% yield). MS (apci) m/z=251.8 (M+H).

Intermediate 157

3-amino-5-methyl-2-phenyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-oneStep A: Preparation of ethyl5-amino-4-((methylamino)methyl)-1-phenyl-1H-pyrazole-3-carboxylate

To a stirred solution of ethyl5-amino-4-formyl-1-phenyl-1H-pyrazole-3-carboxylate (Prepared accordingto the procedure described in J. Heterocyclic Chemistry, 2010, 47, p.287-291, 142 mg, 0.548 mmol) in DCM (3 mL) was added 2.0 M MeNH₂ in THF(0.822 mL, 1.64 mmol). Two drops of acetic acid was added. The reactionmixture was stirred at ambient temperature overnight. MeOH (0.4 mL) wasadded followed by NaBH₄ (31 mg, 0.82 mmol) portionwise. The reaction wasquenched by the slow addition of water. The mixture was extracted withDCM. The combined organic layers were washed with brine, dried andconcentrated. The crude was used in the next step without furtherpurification. MS (apci) m/z=275.0 (M+H).

Step B: Preparation of3-amino-5-methyl-2-phenyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one

To a stirred solution of ethyl5-amino-4-((methylamino)methyl)-1-phenyl-1H-pyrazole-3-carboxylate(crude, 65 mg, 0.24 mmol) in MeOH (0.5 mL) and THF (0.5 mL) was added 2N NaOH (0.24 mL, 0.47 mmol). The reaction mixture was stirred at ambienttemperature for 4 hours and then concentrated in vacuo. To the residuewas added water. The pH was adjusted to 4-5 using 1 N HCl. Water wasevaporated under reduced pressure. The crude acid (58 mg) was dissolvedin DMF (3 mL). Et₃N (66 μL, 0.47 mmol) was added followed by EDCI (90mg, 0.47 mmol) and HOBt (32 mg, 0.24 mmol). The reaction mixture wasstirred at ambient temperature overnight and then partitioned betweenEtOAc and water. The aqueous layer was extracted with EtOAc. Thecombined organic layers were washed with water and brine, dried andconcentrated. The residue was purified by flash chromatography on silicagel (2% MeOH in DCM) to give the title compound (15 mg, 28%) as a whitesolid. MS (apci) m/z=228.9 (M+H).

Intermediate 158

3-methyl-4-(methylthio)-1-phenyl-1H-pyrazol-5-amine

Prepared according to the method described for Intermediate P109,replacing methyl 2-methoxyacetate with ethyl acetate and replacingacetonitrile with 2-(methylthio)acetonitrile in Step A to afford theproduct as a brown oil. MS (apci) m/z=220.1 (M+H).

Intermediate 159

2-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-2,2-difluoroethanol

Prepared according to the method described for Intermediate P111,replacing acetonitrile with propionitrile and replacing methyl3-hydroxy-2,2-dimethylpropanoate with ethyl2,2-difluoro-3-hydroxypropanoate to afford the product as a pale yellowsolid. MS (apci) m/z=254.1 (M+H).

Intermediate 160

2-(5-amino-1-phenyl-1H-pyrazol-3-yl)-2,2-difluoroethanol

Prepared according to the method described for Intermediate P111,replacing methyl 3-hydroxy-2,2-dimethylpropanoate with ethyl2,2-difluoro-3-hydroxypropanoate to afford the product as a pale yellowsolid. MS (apci) m/z=240.0 (M+H).

Intermediate 161

2-(5-amino-1-phenyl-1H-pyrazol-3-yl)ethanol

Prepared according to the method described in Intermediate P111,replacing methyl 3-hydroxy-2,2-dimethylpropanoate with methyl3-hydroxypropanoate in Step A. MS (apci) m/z=204.1 (M+H).

Intermediate 162

1-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-2-methylpropan-2-ol StepA: Preparation of ethyl 3-hydroxy-3-methylbutanoate

To a solution of lithium bis(trimethylsilyl)amide (1M in THF) (100 mL,100 mmol) in THF (100 mL) under N₂ and cooled to −78° C. was added ethylacetate (9.74 mL, 100 mmol). The reaction mixture was stirred for 30minutes, and then acetone (8.81 mL, 120 mmol) was added. The reactionmixture was stirred for 10 minutes, and then quenched with HCl (2Maqueous, 70 mL, 140 mmol) and allowed to warm to ambient temperature.The reaction mixture was extracted with EtOAc (2×150 mL). The organicphases were combined and washed with saturated aqueous NaHCO₃ (2×50 mL),dried (MgSO₄), filtered and concentrated to afford the product as ayellow oil (12.8 g, 88% yield). ¹H NMR (CDCl₃) δ 4.18 (q, 3H), 2.49 (s,2H), 1.29 (m, 9H).

Step B: Preparation of 5-hydroxy-5-methyl-3-oxohexanenitrile

To a solution of propionitrile (1.77 mL, 30.5 mmol) in THF (100 mL)under N₂ at −78° C. was added lithium bis(trimethylsilyl)amide (1M inTHF) (27.9 mL, 27.9 mmol). Stirred 1 hour, then ethyl3-hydroxy-3-methylbutanoate (1.86 g, 12.7 mmol) was added. The reactionmixture was stirred at −78° C. for 1 hour, then stirred at 0° C. for 1.5hours, then diluted with H₂O (100 mL) and extracted with Et₂O (50 mL).The phases were separated and the basic aqueous phase was neutralizedwith HCl (6M aqueous, 4.5 mL), then extracted with Et₂O (3×75 mL). Thecombined organic phases were washed with brine (75 mL), dried (MgSO₄),filtered, and concentrated to afford the product as a pale yellow oil(1.24 g, 63% yield). ¹H NMR (CDCl₃) δ 3.54 (m, 1H), 2.89 (s, 2H), 1.50(d, 3H), 1.32 (s, 3H), 1.31 (s, 3H).

Step C: Preparation of1-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-2-methylpropan-2-ol

To a suspension of phenylhydrazine (0.793 mL, 7.99 mmol) and HCl (5-6Min iPrOH, 1.60 mL, 7.99 mmol) in EtOH (25 mL) was added a solution of5-hydroxy-2,5-dimethyl-3-oxohexanenitrile (1.24 g, 7.99 mmol) in EtOH(25 mL). The reaction mixture was refluxed for 17 hours, then cooled toambient temperature, diluted with saturated aqueous NaHCO₃ (10 mL),extracted 10:90 MeOH/DCM (3×25 mL), and the combined organic phases weredried (MgSO₄), filtered and concentrated. Purified by silica columnchromatography eluting with 0-75% acetone/hexanes to afford the titlecompound as an orange oil (1.13 g, 58% yield). MS (apci) m/z=246.1(M+H).

The following pyrazole intermediates were prepared according to themethod used for the preparation of Intermediate 162, Steps B and C,using the appropriate starting material. For the preparation ofIntermediates 168 and 169, the starting material (purchased fromOakwood) was a mixture of cis and trans diastereomers.

Intermediate # Structure Name MS (apci) m/z 163

1-(5-amino-1-phenyl-1H- pyrazol-3-yl)-2- methylpropan-2-ol 232.1 (M + H)164

(S)-1-(5-amino-4-methyl-1- phenyl-1H-pyrazol-3- yl)propan-2-ol 232.1(M + H) 165

(S)-1-(5-amino-1-phenyl-1H- pyrazol-3-yl)propan-2-ol 218.1 (M + H) 166

(R)-1-(5-amino-4-methyl-1- phenyl-1H-pyrazol-3- yl)propan-2-ol 232.1(M + H) 167

(R)-1-(5-amino-1-phenyl-1H- pyrazol-3-yl)propan-2-ol 218.1 (M + H) 168

3-(5-amino-4-methyl-1- phenyl-1H-pyrazol-3- yl)cyclobutanol 244.1 (M +H) 169

3-(5-amino-1-phenyl-1H- pyrazol-3-yl)cyclobutanol 230.1 (M + H)

Intermediate 170

ethyl 5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylate

Prepared according to the method described for Intermediate P109,replacing methyl 2-methoxyacetate with diethyl oxalate and replacingacetonitrile with propionitrile in Step A to afford the product as ayellow solid. MS (apci) m/z=246.1 (M+H).

Intermediate 171

5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid

To a solution of ethyl5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylate (Intermediate 170,1.52 mg, 6.21 mmol) in THF (12 mL) and MeOH (6 mL) was added LiOH (2Maq, 9.31 mL, 18.6 mmol). The reaction mixture was stirred at ambienttemperature for 19 hours, then partially concentrated under reducedpressure, then neutralized with 6M HCl (3.2 mL), extracted with 10:90MeOH/DCM (3×25 mL), and the combined organic extracts were washed withbrine (50 mL), dried (MgSO₄), filtered and concentrated to give thetitle compound as a yellow solid (1.3 g, 96% yield) MS (apci) m/z=218.1(M+H).

Intermediate 172

5-amino-N,4-dimethyl-1-phenyl-1H-pyrazole-3-carboxamide

To a solution of 5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid(Intermediate 171, 223 mg, 1.02 mmol) in acetonitrile (10 mL) were addedDIEA (0.71 mL, 4.10 mmol), methanamine hydrochloride (138 mg, 2.05mmol), DMF (2 mL), and then HATU (428 mg, 1.13 mmol). The reactionmixture was stirred at ambient temperature for 19 hours and thenpartially concentrated under reduced pressure. The mixture was purifiedby reverse-phase column chromatography, eluting with 5-60%acetonitrile/water to afford the title compound as a pale yellow solid(182 mg, 77% yield). MS (apci) m/z=231.1 (M+H).

Intermediate 173

5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxamide

A solution of 5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carbonitrile (150mg, 0.757 mmol) in concentrated H₂SO₄ (0.5 mL) was stirred at ambienttemperature for 17 hours. The reaction mixture was cooled andneutralized by the addition of aqueous NaOH (2M, 11 mL), then extracted10% MeOH/DCM (5×10 mL), and the combined organic extracts were washedwith brine, dried (MgSO₄), filtered and concentrated under reducedpressure to afford the title compound as a white solid (151 mg, 95%yield). MS (apci) m/z=239.1 (M+Na).

Intermediate 174

ethyl 5-amino-3-ethoxy-1-phenyl-1H-pyrazole-4-carboxylate Step A:Preparation of diethyl 2-cyanomalonate

To a suspension of NaH (60 wt % in mineral oil, 499 mg, 12.49 mmol) inTHF (100 mL) under N₂ at 0° C. was added diethyl malonate (1.90 mL,12.49 mmol). The ice bath was removed and the reaction mixture wasstirred at ambient temperature for 30 minutes, then cooled to 0° C. andcyanic bromide (5M in MeCN, 2.5 mL, 12.49 mmol) was added. The reactionmixture was stirred at ambient temperature for 19 hours, then dilutedwith H₂O (50 mL), extracted with Et₂O (50 mL). The aqueous phase wasneutralized with HCl (2M aq, 3 mL) then extracted with DCM (2×50 mL).The combined DCM extracts were dried (MgSO₄), filtered, and concentratedto afford the product as a yellow oil (837 mg, 36% yield). 1H NMR(CDCl₃) δ 4.46 (s, 1H), 4.35 (q, 4H), 1.35 (t, 6H).

Step B: Preparation of ethyl5-amino-3-ethoxy-1-phenyl-1H-pyrazole-4-carboxylate

Prepared according to the method described for Intermediate P135,replacing ethyl 2-cyanopropanoate with diethyl 2-cyanomalonate in Step Ato afford the product as a brown syrup (400 mg, 32% yield). MS (apci)m/z=276.1 (M+H).

Intermediate 175

4-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1-phenyl-1H-pyrazol-5-amineStep A: Preparation ofN′-acetyl-5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carbohydrazide

To a solution of 5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid(Intermediate 171, 93 mg, 0.428 mmol) in DCM (5 mL) and DIEA (0.149 mL,0.856 mmol) was added isobutyl carbonochloridate (0.061 mL, 0.471 mmol).The reaction mixture was stirred at ambient temperature for 1 hour, thenacetohydrazide (48 mg, 0.642 mmol) was added. The reaction mixture wasstirred at ambient temperature for 18 hours, then diluted with H₂O (10mL), extracted DCM (2×10 mL), dried (MgSO₄), filtered and concentratedunder reduced pressure to afford the product as a pale yellow solid (119mg, 101% yield). MS (apci) m/z=274.1 (M+H).

Step B: Preparation of4-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1-phenyl-1H-pyrazol-5-amine

A mixture ofN′-acetyl-5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carbohydrazide (117mg, 0.428 mmol) and POCl₃ (0.5 mL) was heated in a pressure tube to 90°C. for 1 hour. The reaction mixture was transferred to a separatoryfunnel with EtOAc (5 mL), then diluted with saturated aqueous NaHCO₃ (20mL), extracted with EtOAc (2×15 mL), dried (MgSO₄), filtered andconcentrated. The residue was purified by silica column chromatographyeluting with 0-75% acetone/hexanes to afford the title compound as ayellow solid (19.6 mg, 18% yield). MS (apci) m/z=256.1 (M+H).

Intermediate 176

4-methyl-3-(3-methyl-1, 2,4-oxadiazol-5-yl)-1-phenyl-1H-pyrazol-5-amine

To a suspension of NaH (60% in mineral oil, 36 mg, 0.897 mmol) in THF (5mL) under N₂ was added N-hydroxyacetimidamide (66 mg, 0.897 mmol). Thereaction mixture was heated to reflux for 1 hour, then cooled to ambienttemperature and ethyl5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylate (Intermediate 170,200 mg, 0.815 mmol) was added. The reaction mixture was heated to refluxfor 18 hours, then cooled to ambient temperature and additional NaH (60%in mineral oil, 18 mg, 0.449 mmol) was added. The reaction mixture washeated to reflux for 4 hours, then diluted with H₂O (10 mL), extractedDCM (2×15 mL), and the combined organic extracts were dried (MgSO₄),filtered and concentrated under reduced pressure. The residue waspurified by silica column chromatography eluting with 0-50%acetone/hexanes to afford the title compound as an orange solid (84 mg,40% yield). MS (apci) m/z=256.1 (M+H).

Intermediate 177

3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-phenyl-1H-pyrazol-5-amine

Prepared according to the method described in Intermediate 176,replacing ethyl 5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylate withethyl 5-amino-1-phenyl-1H-pyrazole-3-carboxylate (Nanjing ChemlinChemical Co.) to afford the product as a tan solid (83 mg, 53% yield).MS (apci) m/z=242.1 (M+H).

Intermediate 178

4-methyl-1-phenyl-3-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-5-amineStep A: Preparation of 2,2,2-trifluoro-N′-hydroxyacetimidamide

To a suspension of hydroxylamine hydrochloride (5.45 g, 78.4 mmol) inMeOH (100 mL) was added NaOMe (25 wt % solution in MeOH, 17.9 mL, 78.4mmol) and the mixture stirred at ambient temperature for 10 minutes,then filtered and the solid was washed with MeOH. The filtrate wascooled to 0° C. and then 2,2,2-trifluoroacetonitrile (7.45 g, 78.4 mmol)gas was bubbled into the solution over 30 minutes. The reaction mixturewas then allowed to warm to ambient temperature for 19 hours. Thesolution was concentrated under reduced pressure to 50 mL and the solidswere filtered. The filtrate was concentrated, re-suspended in cold MeOH,and filtered. The filtrate was concentrated, again re-suspended in coldMeOH, and filtered. The filtrate was concentrated to give the product asa waxy white solid (6.7 g, 67% yield). ¹H NMR (CD₃CN) δ 8.32 (s, 1H),5.25 (br s, 2H). 19F NMR (CD₃CN) 6-71.8 (s).

Step B: Preparation of4-methyl-1-phenyl-3-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-5-amine

To a suspension of NaH (60% in mineral oil, 356 mg, 0.897 mmol) in THF(5 mL, 0.815 mmol) under N₂ was added2,2,2-trifluoro-N′-hydroxyacetimidamide (115 mg, 0.897 mmol). Thereaction mixture was heated to reflux for 1 hour, then cooled to ambienttemperature and powdered 4A molecular sieves (200 mg) and ethyl5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylate (Intermediate 170;200 mg, 0.815 mmol) were added and heated to reflux. The reactionmixture was heated to reflux for 18 hours, then filtered, diluted withH₂O (15 mL), extracted DCM (2×25 mL), and the combined organic extractswere washed with brine (25 mL), dried (MgSO₄), filtered and concentratedunder reduced pressure. The residue was purified by silica columnchromatography eluting with 0-50% acetone/hexanes to afford the titlecompound as a white solid (44 mg, 17% yield). MS (apci) m/z=310.1 (M+H).

Intermediate 179

2-phenyl-2H-indazol-3-amine Step A: Preparation of1-(2-iodophenyl)-2-phenyldiazene

To a solution of 2-iodoaniline (1.00 g, 4.57 mmol) in acetic acid (46mL) was added nitrosobenzene (0.880 g, 8.22 mmol) and the mixture washeated at 85° C. for 16 hours. The mixture was cooled to ambienttemperature, poured into water and slowly treated with saturated NaHCO₃until basic. The mixture was extracted with EtOAc (3×) and the combinedextracts were washed with water, saturated NaCl and dried over MgSO₄.The solution was filtered, concentrated and the residue purified byreverse phase chromatography to provide the title compound as a redsolid (0.880 g, 63% yield). ¹H NMR (CDCl₃) δ 7.23-7.39 (m, 3H), 7.64 (d,1H), 7.56-7.51 (m, 3H), 7.45 (t, 1H), 7.1 (t, 1H).

Step B: 2-(phenyldiazenyl)benzonitrile

To a solution of 1-(2-iodophenyl)-2-phenyldiazene (0.44 g, 1.4 mmol) in1-propanol (14 mL) was added CuCN (0.900 g, 10.0 mmol) and the reactionwas heated at reflux for 16 hours. The mixture was cooled to ambienttemperature, filtered and the collected solid washed with CH₂Cl₂. Thecombined filtrate and washes were concentrated to provide the titlecompound as red-orange solid that was dried in vacuum (0.280 g, 95%yield). ¹H NMR (CDCl₃) δ 8.03-8.06 (m, 2H), 7.88 (dd, 2H), 7.71 (t, 1H),7.54-7.58 (m, 4H).

Step C: 2-phenyl-2H-indazol-3-amine

A mixture of 2-(phenyldiazenyl)benzonitrile (0.28 g, 1.35 mmol) andSnCl₂ dihydrate (0.562 mL, 6.76 mmol) in EtOH (14 mL) was heated atreflux for 16 hours. The mixture was cooled to ambient temperature andconcentrated. The residue was diluted with EtOAc and water and filtered.The aqueous layer was removed and the EtOAc layer was washed with water.The combined aqueous fractions were basified with saturated NaHCO₃ andextracted with CH₂Cl₂ (2×). The combined organic layers were dried overMgSO₄, filtered and concentrated to provide the title compound as alight purple solid that was dried in vacuum (0.241 g, 85% yield). ¹H NMR(CDCl₃) δ 7.69 (d, 2H), 7.52-7.58 (m, 3H), 7.47 (d, 2H), 7.26 (t, 1H),6.90 (t, 1H), 4.28 (br s, 2H).

Intermediate 180

3-ethoxy-4-methyl-1-(pyrazin-2-yl)-1H-pyrazol-5-amine Step A:5-amino-4-methyl-1-(pyrazin-2-yl)-1H-pyrazol-3 (2H)-one

To a mixture of 2-hydrazinylpyrazine (0.551 g, 5.00 mmol) and ethyl2-cyanopropanoate (0.669 g, 5.00 mmol) in abs. EtOH (10 mL) was added 3MNaOEt in EtOH (0.167 mL, 0.501 mmol) and the mixture was heated atreflux for 64 hours. The mixture was concentrated and the residualyellow-brown solid was treated with EtOAc (30 mL) and sonicated. Theresulting tan suspension was stirred vigorously for 8 hours. The solidwas collected via vacuum filtration, washed with EtOAc and dried invacuum to afford the title compound as a light tan powder (682 mg, 71%).¹H NMR (DMSO d₆) δ 10.3 (br s, 1H), 8.82 (s, 1H), 8.30 (d, 2H), 6.55 (s,2H), 1.71 (s, 3H).

Step B: 3-ethoxy-4-methyl-1-(pyrazin-2-yl)-1H-pyrazol-5-amine

A mixture of 5-amino-4-methyl-1-(pyrazin-2-yl)-1H-pyrazol-3(2H)-one (382mg, 2.00 mmol) and powdered K₂CO₃ (552 mg, 4.00 mmol) in dry DMF (3.0mL) was stirred at ambient temperature for 10 minutes. The mixture wascooled to 0° C. and bromoethane (229 mg, 2.10 mmol) was added. Themixture was allowed to reach ambient temperature and was stirred 24hours. The reaction mixture poured into cold H₂O (12 mL), allowed toreach ambient temperature and was extracted with EtOAc (3×). Thecombined extracts were washed with saturated NaCl (2×), dried over MgSO₄and activated carbon. The dried solution was diluted with and equalvolume of hexanes and filtered through a SiO₂ plug capped with a MgSO₄layer eluting with 50% EtOAc-hexanes. The filtrate was concentrated andthe residual yellow solid was washed with hexanes (3×) and dried invacuum to afford the title compound as a light yellow crystalline solid(195 mg, 45%). ¹H NMR (CDCl₃) δ 9.10 (s, 1H), 8.23 (s, 1H), 8.14 (s,1H), 5.50 (br s, 2H), 4.33 (q, 2H), 1.80 (s, 3H), 1.42 (t, 3H).

Intermediate 181

2-(pyridazin-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine

A suspension of 4-hydrazinylpyridazine hydrobromide (0.368 g, 1.93 mmol)in absolute EtOH (5 mL) was treated with 2-oxocyclopentanecarbonitrile(0.191 g, 1.75 mmol) and the mixture was heated at reflux for 22 hours.The mixture was cooled to ambient temperature and was concentrated to anorange solid. The solid was suspended in 1M NaOH and stirred for 10minutes. The solid was collected, washed thoroughly with H₂O and Et₂Oand dried in vacuum to furnish title compound as a tan powder (0.323 g,92%). MS (apci) m/z=202.1 (M+H).

Intermediate 182

(5-amino-1-phenyl-1H-pyrazol-3-yl)methanol Step A: Ethyl2-(tert-butyldimethylsilyloxy)acetate

A mixture of ethyl 2-hydroxyacetate (3.00 g, 28.8 mmol), TBDMS-Cl (5.21g, 34.6 mmol) and imidazole (2.55 g, 37.5 mmol) was stirred at ambienttemperature for 60 hours. The mixture was concentrated and the residuewas purified by SiO₂ chromatography eluting with 10% EtOAc-hexanes toprovide the title compound as a colorless oil (4.12 g, 65%). ¹H NMR(CDCl₃) δ 4.12 (s, 2H), 4.09 (q, 2H), 1.17 (t, 3H), 0.18 (s, 9H), 0.00(s, 6H).

Step B: (5-amino-1-phenyl-1H-pyrazol-3-yl)methanol

A solution of acetonitrile (0.526 mL, 10.1 mmol) in dry THF (20.4 mL,9.16 mmol) was cooled to −78° C. and 2.5M nBuLi in hexanes (4.21 mL,10.5 mmol) was added dropwise. The reaction mixture was stirred for 15minutes and ethyl 2-(tert-butyldimethylsilyloxy)acetate (2.00 g, 9.16mmol) was added. The reaction mixture was allowed to warm to ambienttemperature and was stirred for 2 hours. The reaction mixture wasdiluted with ice water and was concentrated. The residual aqueousmixture was acidified to pH=5 and extracted with EtOAc (3×). Thecombined organics were washed with brine, dried over MgSO₄, filtered andconcentrated. The residual brown oil was dissolved in MeOH (23 mL) andphenyl hydrazine (0.907 mL, 9.14 mmol) was added. The mixture wastreated with concentrated HCl (3.81 mL, 45.7 mmol) and heated at refluxfor 18 hours. Upon cooling, the mixture was concentrated and the residuewas partitioned into in H₂O and CH₂Cl₂. The mixture was filtered and theorganic layer was removed from the filtrate. The aqueous portion waswashed with CH₂Cl₂ and was treated with saturated NaHCO₃ until basic.The aqueous mixture was extracted with CH₂Cl₂ (3×) and the combinedorganic fractions were dried over MgSO₄, filtered and concentrated. Theresidue was purified by silica column chromatography using 70-100%EtOAc/hexanes gradient elution followed by 0-5% MeOH/EtOAc. The productpools were combined and concentrated to give the title compound as ayellow foam (0.760 g, 44% yield). MS (apci) m/z=190.1 (M+H).

Intermediate 183

4-methyl-3-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)-1-phenyl-1H-pyrazol-5-amine

The title compound was prepared by the method as described forIntermediate P135, substituting bromoethane with3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride. The productwas isolated as a gold syrup (110 mg, 27%). MS (apci) m/z=285.1 (M+H).

Intermediate 184

5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl dimethylcarbamate

A mixture of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one(Intermediate P135 Step A, 0.378 g, 2.00 mmol) and powdered K₂CO₃ (0.553g, 4.00 mmol) in dry DMF (4 mL) was stirred at ambient temperature for 5minutes. Dimethylcarbamoyl chloride (0.206 mL, 2.20 mmol) was added andthe mixture was stirred for 6 hours. The mixture was poured into chilledH₂O (40 mL) and was extracted with EtOAc (3×). The combined extractswere washed with saturated NaCl (2×), dried over MgSO₄ and filteredthrough a SiO₂ plug capped with a MgSO₄ layer (EtOAc elution). Thefiltrate was concentrated and the residue dried in vacuum to give thetitle compound as a light gold syrup (0.507 g, 97%). MS (apci) m/z=261.1(M+H).

Intermediate 185

5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl morpholine-4-carboxylate

The title compound was prepared using morpholine-4-carbonyl chloride inthe procedure outlined for 5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yldimethylcarbamate (Intermediate 184). The compound was isolated as alight yellow wax (0.285 g, 47%). ¹H NMR (CDCl₃) δ 7.54 (d, 2H), 7.43 (t,2H), 7.31 (t, 1H), 3.66-3.78 (m, 8H), 3.57 (br s, 2H), 1.85 (s, 3H).

Intermediate 186

(S)-3-(2-((tert-butyldimethylsilyl)oxy)-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-amineStep A:(S)-1-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yloxy)-3-methoxypropan-2-ol

A mixture of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3 (2H)-one (P135 StepA, 1.21 g, 6.40 mmol) and powdered K₂CO₃ (1.77 g, 12.8 mmol) in dry DMF(12 mL) was stirred at ambient temperature for 10 minutes.(S)-2-(methoxymethyl)oxirane (0.622 mL, 6.72 mmol) was added and themixture was stirred at 80° C. for 6 hours. The mixture was cooled toambient temperature, poured into chilled H₂O (25 mL) and extracted withEtOAc (3×). The combined extracts were washed with saturated NaCl (2×),dried over MgSO₄ and filtered through a SiO₂ plug capped with a layer ofMgSO₄ eluting with EtOAc. The filtrate was concentrated to give thetitle compound as a colorless, viscous oil (701 mg, 40%). MS (apci)m/z=278.1 (M+H).

Step B:(S)-3-(2-((tert-butyldimethylsilyl)oxy)-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-amine

To a solution of TBDMS-Cl (725 mg, 4.81 mmol) and imidazole (390 mg,5.72 mmol) in dry DMF (7.0 mL) was added(S)-1-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yloxy)-3-methoxypropan-2-ol(635 mg, 2.29 mmol) in dry DMF (2 mL). The mixture stirred at ambienttemperature for 2.5 hours. The mixture added to H₂O (70 mL), mixed for 5minutes and extracted with Et₂O (3×). The combined extracts were washedwith saturated NaCl (2×) and dried over MgSO₄. The dried solution wasfiltered through a SiO₂ plug capped with a layer of MgSO₄ (Et₂Oelution). The filtrate was concentrated to give the title compound as acolorless oil that was dried in vacuum (940 mg, 105%). MS (apci)m/z=392.2 (M+H). ¹H NMR (CDCl₃) δ 7.50 (d, 2H), 7.40 (t, 2H), 7.23 (t,1H), 4.09-4.30 (m, 3H), 3.57 (br s, 2H), 3.38-3.44 (m, 2H), 3.32 (s,3H), 1.83 (s, 3H), 0.88 (s, 9H), 0.11 (s, 6H).

Intermediate 187

(R)-3-(2-((tert-butyldimethylsilyl)oxy)-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-amine

The title compound was prepared using the procedure described for(S)-3-(2-((tert-butyldimethylsilyl)oxy)-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-amine(Intermediate 186) substituting (S)-2-(methoxymethyl)oxirane with(R)-2-(methoxymethyl)oxirane in Step A. The product was obtained as acolorless syrup (921 mg, 38% over 2 steps). MS (apci) m/z=392.2 (M+H).¹H NMR (CDCl₃) δ 7.50 (d, 2H), 7.40 (t, 2H), 7.23 (t, 1H), 4.09-4.30 (m,3H), 3.57 (br s, 2H), 3.38-3.44 (m, 2H), 3.32 (s, 3H), 1.83 (s, 3H),0.88 (s, 9H), 0.11 (s, 6H).

Intermediate 188

tert-butyl4-((5-amino-1-phenyl-1H-pyrazol-3-yl)methoxy)piperidine-1-carboxylateStep A: tert-butyl 4-(2-ethoxy-2-oxoethoxy)piperidine-1-carboxylate

A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.00 g, 9.94mmol) in dry THF (25 mL) was cooled to 0° C. and KOtBu (1.12 g, 9.94mmol) was added. The mixture was allowed to reach ambient temperatureand was stirred for 10 minutes. The mixture was cooled to 0° C. andethyl 2-bromoacetate (1.65 mL, 14.9 mmol) was added dropwise. Thereaction was allowed to reach ambient temperature and was stirred for 17hours. The mixture was partitioned into in H₂O and EtOAc, mixed and theorganic layer was removed. The organic layer was dried over MgSO₄,filtered and concentrated. The residual thick yellow oil was purified bysilica chromatography using a 10-25% EtOAc/hexanes gradient elution toafford the title compound as a colorless oil (0.967 g, 34% yield). ¹HNMR (CDCl₃) δ 4.22 (q, 2H), 4.12 (s, 2H), 3.67-3.84 (m, 2H), 3.52-3.63(m, 1H), 3.05-3.11 (m, 2H), 1.81-1.90 (m, 2H), 1.53-1.62 (m, 2H), 1.45(s, 9H), 1.29 (t, 3H).

Step B: tert-butyl4-((5-amino-1-phenyl-1H-pyrazol-3-yl)methoxy)piperidine-1-carboxylate

A solution of diisopropylamine (1.08 mL, 7.74 mmol) in dry THF (5 mL)was cooled to 0° C. and 2.5M nBuLi in hexanes (2.96 mL, 7.41 mmol) wasslowly added. The mixture was stirred at 0° C. for 10 minutes and wascooled to −78° C. Acetonitrile (0.404 mL, 7.74 mmol) was added and themixture was stirred for 15 minutes. A solution of tert-butyl4-(2-ethoxy-2-oxoethoxy)piperidine-1-carboxylate (0.967 g, 3.37 mmol) inTHF (2.5 mL) was added and the mixture was stirred at −78° C. for 1hour. The mixture was allowed to reach ambient temperature, was quenchedwith ice water and concentrated. The residual aqueous mixture wasneutralized with 2M HCl and was extracted with CH₂Cl₂ (3×). The combinedorganic fractions were dried over MgSO₄, filtered and concentrated toprovide the crude cyano-ketone as a yellow oil that was used immediatelyin the next step.

Step C: tert-butyl4-((5-amino-1-phenyl-1H-pyrazol-3-yl)methoxy)piperidine-1-carboxylate

The crude oil obtained in Step B was dissolved in EtOH (17 mL) andphenylhydrazine (0.396 mL, 3.99 mmol) was added. The mixture was heatedat 60° C. for 60 hours, was cooled to ambient temperature and wasconcentrated. The residue was partitioned into EtOAc and water, mixedand the organic layer removed. The aqueous layer was extracted withEtOAc (2×) and the combined EtOAc portions were dried over MgSO₄,filtered and concentrated. The residual orange oil was purified bysilica chromatography using a 10-100% EtOAc/hexanes gradient elution.The pooled product fractions were concentrated and the residualyellow-orange oil was re-purified by reverse phase HPLC using a 0-100%acetonitrile/water gradient to provide the title compound as an orangefoam (0.264 g, 21% yield). MS (apci) m/z=373.2 (M+H).

Intermediate 189

1-phenyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine Step A:3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanenitrile

A 1M solution of LHMDS in dry THF (26.3 mL, 26.3 mmol) was cooled to−78° C. and acetonitrile (1.43 mL, 27.5 mmol) was added dropwise over 2minutes. The mixture was stirred at −78° C. for 1 hour and a solution ofmethyl tetrahydro-2H-pyran-4-carboxylate (3.41 mL, 25.0 mmol) in dry THF(12 mL) was added. The mixture was stirred for 1 hour, the dry ice bathwas removed and the mixture allowed to reach ambient temperature. Themixture was poured into chilled H₂O (250 mL) and was extracted with Et₂O(3×). The aqueous portion was cooled to 0° C. and 6M HCl was addeddropwise to pH=3 (starting pH=12). The mixture was extracted with EtOAc(3×) and the combined extracts were dried over MgSO₄. The solutioneluted through a SiO₂ plug eluting with EtOAc. The filtrate wasconcentrated to give the title compound as a colorless oil (2.52 g,66%). ¹H NMR (CDCl₃) δ 3.99-4.06 (m, 2H), 3.54 (s, 2H), 3.46 (t, 2H),2.76-2.86 (m, 1H), 1.70-1.86 (m, 4H).

Step B: 1-phenyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine

To a solution of 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanenitrile (2.30g, 12.8 mmol) in absolute EtOH (35 mL) was added phenylhydrazinehydrochloride (2.21 g, 15.3 mmol) and the mixture was heated at refluxuntil complete by TLC (5 hours). The mixture was cooled to ambienttemperature and was concentrated. The residue was partitioned in H₂O (75mL) and EtOAc (40 mL). 2M NaOH was added to pH=5 with vigorous mixing,the organic layer was removed and the aqueous was extracted with EtOAc(2×). The combined EtOAc fractions were washed with H₂O and saturatedNaCl. The solution was diluted with an equal volume of hexanes, driedover MgSO₄/activated carbon and eluted through a SiO₂ plug eluting with50% EtOAc-hexanes. The filtrate was concentrated to give a gold syrup.The syrup was treated with Et₂O and stirred until a fine, granularsuspension formed. The solid was collected, washed with Et₂O and driedin vacuum to furnish the title compound as a white solid (2.01 g, 65%).¹H NMR (CDCl₃) δ 7.55 (d, 2H), 7.46 (t, 2H), 7.32 (t, 1H), 5.49 (s, 1H),4.00-4.08 (m, 2H), 3.97 (br s, 2H), 3.52 (dt, 2H), 2.86 (m, 1H)1.73-1.93 (m, 4H).

The following compounds were prepared according to the method used forthe preparation of1-phenyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine (Intermediate189) using either acetonitrile or propiononitrile in Step A inconjunction with the appropriate ester.

Intermediate # Structure Data 190

MS (apci) m/z = 343.1 (M + H) 191

MS (apci) m/z = 258.0 (M + H) 192

¹H NMR (CDCl₃) δ 7.62 (d, 2H), 7.50 (t, 2H), 7.37 (t, 1H), 5.72 (s, 1H),3.91 (br s, 2H), 2.58 (s, 3H), 2.44 (s, 3H). 193

¹H NMR (CDCl₃) δ 7.60 (d, 2H), 7.49 (t, 2H), 7.37 (t, 1H), 6.45 (s, 1H),3.67 (br s, 2H), 2.45 (s, 3H), 2.24 (s, 3H). 194

¹H NMR (CDCl₃) δ 7.45-7.56 (m, 4H), 7.35 (t, 1H), 4.00-4.06 (m, 2H),3.88 (dt, 2H), 3.62 (br s, 2H), 2.18-2.34 (m, 4H), 2.11 (s, 3H). 195

MS (apci) m/z = 343.2 (M + H) 196

MS (apci) m/z = 343.2 (M + H) 197

MS (apci) m/z = 329.2 (M + H) 198

MS (apci) m/z = 329.2 (M + H)

Intermediate 199

Phenyl 1′,4-dimethyl-1-phenyl-1H, 1′H-3,4′-bipyrazol-5-ylcarbamate StepA: ethyl 1-methyl-1H-pyrazole-4-carboxylate

To a 3000-mL three-necked flask was added ethyl 2-formyl-3-oxopropanoate(100 g, 694 mmol), followed by anhydrous 200-proof EtOH (694 mL) toobtain a clear yellowish solution. The reaction was cooled in an icebath to 5° C., and then methylhydrazine (35.8 mL, 680 mmol) was addeddropwise. A vigorous exotherm was observed during hydrazine addition andthe temperature was kept below 12° C. by controlling the addition rate.After the hydrazine addition was complete, the ice bath was removed, andthe reaction was allowed to stir at ambient temperature overnight. Thereaction was concentrated on a rotary evaporator to a crude orange oil.The crude was taken up in DCM and re-concentrated, then on high vacuumfor 2 days to yield tan orange oil. LC/MS and ¹H NMR showed essentiallypure ethyl 1-methyl-1H-pyrazole-4-carboxylate (106 g, 99.1%).

Step B: 2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropanenitrile

To a four-necked 5-liter round bottomed flask fitted with an overheadstirrer and addition funnel was charged LHMDS (1444 mL, 1444 mmol) (1.0Min THF). The solution was cooled in an acetone/dry ice bath first(internal temperature of −79° C.) under nitrogen, followed by slowaddition of propiononitrile (103 mL, 1444 mmol) via dropping funnel. Themixture was stirred at −80° C. for 90 minutes. A solution of ethyl1-methyl-1H-pyrazole-4-carboxylate (106 g, 688 mmol) in anhydrous THF(500 mL) was then introduced dropwise via an addition funnel (additiontime: about 45 minutes; internal temperature during addition remainedbelow −76° C.). After the addition was complete, the reaction wasallowed to slowly warm to ambient temperature and stirred overnight. Anorange glass deposited on the bottom of the flask. The organics weredecanted and the glass was dissolved in warm water. The mixture waswashed with ether (3×1000 mL). The aqueous phase was then pH-adjusted to5 (pH paper) using concentrated HCl and saturated bicarbarbonatesolution The aqueous layer was extracted with DCM (3×1000 mL). Thecombined organic extracts were dried over MgSO₄ filtered andconcentrated to yield the2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropanenitrile as an amberoil (92 g, 82%). MS (apci) m/z=162.1 (M−H).

Step C: 1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-amine

A 3 L, 3 necked round bottomed flask was charged with2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropanenitrile (60 g, 368mmol) absolute anhydrous ethanol (1000 mL) and phenylhydrazinehydrochloride (58 g, 404 mmol) at ambient temperature to form ayellowish suspension. The reaction vessel was equipped with a watercondenser and refluxed (using a heating mantle) overnight. The reactionwas concentrated and 1M NaOH (1 L) was added and the solid was broken upand collected. The solid was washed with water and hexanes. A secondcrop crashed out in the filtrate and was collected. The combined solidswere crushed and triturated with ether (500 mL). The solid was collectedfiltration, washed with hexanes and air dried under vacuum to provide1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-amine (93 g, 100%).

Step D: phenyl 1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-ylcarbamate

In a 3 L, round bottomed flask was charged with1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-amine (50 g, 197.4 mmol)and EtOAc (1000 mL) to obtain a clear brownish solution. To this wasadded NaOH (2M aq) (500 mL) in one portion to obtain a turbid mixture(both the aqueous and organic layers were clear but a precipitate wasobserved in between the two layers). After 3 minutes, phenylcarbonochloridate (74.29 mL, 592.2 mmol) was added slowly at ambienttemperature exotherm to 33° C. The reaction stirred at ambienttemperature for 2 hours. Additional phenyl carbonochloridate (10 mL) wasadded. After 30 minutes the organics were separated, washed with brineand concentrated in vacuo. The product was purified by silica gelchromatography (eluting with 75% ethyl acetate in hexanes) to providephenyl 1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-ylcarbamate (60 g,81.4%).

Intermediate 200

phenyl 1′,4-dimethyl-1-phenyl-1H, 1′H-3,4′-bipyrazol-5-ylcarbamate

A 3 L, round bottomed flask was charged with1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-amine (50 g, 197.4 mmol)and EtOAc (1000 mL) to obtain a clear brownish solution. To this wasadded NaOH (2M aq) (500 mL) in one portion to obtain a turbid mixture(the aqueous and organic layers were clear, but a precipitate wasobserved in between the two layers). After 3 minutes, phenylcarbonochloridate (74.29 mL, 592.2 mmol) was added slowly at ambienttemperature (the temperature of the reaction mixture increased to 33° C.during the addition). The reaction stirred at ambient temperature for 2hours. Additional phenyl carbonochloridate (10 mL) was added. After 30minutes the organics layers were separated, washed with brine andconcentrated in vacuo. The residue was purified by silica gelchromatography (eluting with 75% ethyl acetate in hexanes) to providephenyl 1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-ylcarbamate (60 g,81.4%).

Intermediate 201

phenyl (4-chloro-3-ethoxy-1-phenyl-1H-pyrazol-5-yl)carbamate Step A:Preparation of phenyl (3-ethoxy-1-phenyl-1H-pyrazol-5-yl)carbamate

To a suspension of 3-ethoxy-1-phenyl-1H-pyrazol-5-amine (IntermediateP139, 169 mg, 0.832 mmol) in EtOAc (5 mL) at 0° C. was added 2.0 Maqueous NaOH solution (1.25 mL, 2.50 mmol), followed by dropwiseaddition of phenyl carbonochloridate (0.178 mL, 1.41 mmol). The reactionwas stirred at ambient temperature for 15 hours. The reaction mixturewas diluted with EtOAc and phase-separated. The organic layer was washedwith water and brine, dried over MgSO₄, and concentrated. The residuewas purified by flash chromatography on silica gel (6:1 hexanes:EtOAc)to give the title compound (219 mg, 81% yield). MS (apci) m/z=324.1(M+H).

Step B: Preparation of phenyl(4-chloro-3-ethoxy-1-phenyl-1H-pyrazol-5-yl)carbamate

To a solution of phenyl 3-ethoxy-1-phenyl-1H-pyrazol-5-ylcarbamate (92mg, 0.28 mmol) and pyridinium 4-methylbenzenesulfonate (7.2 mg, 0.028mmol) in DCM (2 mL) was added N-chlorosuccinimide (42 mg, 0.31 mmol) atambient temperature. The mixture was stirred at ambient temperature for2 days and then concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel (9:1, hexanes/EtOAc) togive the title compound (76 mg, 75% yield). MS (apci) m/z=358.1 (M+H).

Intermediate 202

Phenyl (3-ethoxy-4-fluoro-1-phenyl-1H-pyrazol-5-yl)carbamate

Prepared according to the procedure described in Example 167, step Busing phenyl 3-ethoxy-1-phenyl-1H-pyrazol-5-ylcarbamate as a replacementfor phenyl 3-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate.

Intermediate 203

Phenyl(4-bromo-3-(2-hydroxy-2-methylpropoxy)-1-phenyl-1H-pyrazol-5-yl)carbamateStep A: Preparation of 5-amino-1-phenyl-1H-pyrazol-3 (2H)-one

Prepared according to the method described for Intermediate P1,replacing 4,4-dimethyl-3-oxopentanenitrile with ethyl 2-cyanoacetate,and substituting phenylhydrazine for ethyl 3-hydrazinylbenzoatehydrochloride. MS (apci) m/z=176.0 (M+H).

Step B: Preparation of1-((5-amino-1-phenyl-1H-pyrazol-3-yl)oxy)-2-methylpropan-2-ol

A mixture of 5-amino-1-phenyl-1H-pyrazol-3(2H)-one (0.330 g, 1.88 mmol),2,2-dimethyloxirane (0.143 g, 1.98 mmol) and K₂CO₃ (0.521 g, 3.77 mmol)in DMA (5 mL) was heated at 80° C. for 3 days. After cooling, thereaction mixture was diluted with EtOAc, washed with water and brine anddried over MgSO₄. The mixture was filtered through a pad of SiO₂ elutingwith EtOAc to yield the title compound. MS (apci) m/z=248.1 (M+H).

Step C: Preparation of phenyl(3-(2-hydroxy-2-methylpropoxy)-1-phenyl-1H-pyrazol-5-yl)carbamate

Prepared according to the method described for Intermediate 201. Step Ausing 1-((5-amino-1-phenyl-1H-pyrazol-3-yl)oxy)-2-methylpropan-2-ol as areplacement for 3-ethoxy-1-phenyl-1H-pyrazol-5-amine. MS (apci)m/z=368.1 (M+H).

Step D: Preparation of phenyl(4-bromo-3-(2-hydroxy-2-methylpropoxy)-1-phenyl-1H-pyrazol-5-yl)carbamate

Prepared according to the method described for Intermediate 201, Step Busing N-bromosuccinimide as a replacement for N-chlorosuccinimide, andsubstituting phenyl(3-(2-hydroxy-2-methylpropoxy)-1-phenyl-1H-pyrazol-5-yl)carbamate forphenyl 3-ethoxy-1-phenyl-1H-pyrazol-5-ylcarbamate. MS (apci) m/z=446.1(M+H).

The following compounds prepared according to the method describe forthe preparation of Intermediate 200, using the appropriate aminopyrazole intermediate:

Intermediate # Structure Name Data 204

phenyl 3-(3- methoxypropyl)-4- methyl-1-phenyl-1H- pyrazol-5-ylcarbamateMS (apci) m/z = 366.1 (M + H). 205

phenyl 3-(1,1-difluoro- 2-hydroxyethyl)-4- methyl-1-phenyl-1H-pyrazol-5-ylcarbamate MS (apci) m/z = 374.1 (M + H). 206

(S)-phenyl 3-(2- hydroxypropyl)-4- methyl-1-phenyl-1H-pyrazol-5-ylcarbamate MS (apci) m/z = 352.1 (M + H). 207

(R)-phenyl 3-(2- hydroxypropyl)-4- methyl-1-phenyl-1H-pyrazol-5-ylcarbamate MS (apci) m/z = 352.1 (M + H). 208

phenyl 3-(2-hydroxy-2- methylpropyl)-4- methyl-1-phenyl-1H-pyrazol-5-ylcarbamate MS (apci) m/z = 366.2 (M + H). 209

phenyl 3-(3- hydroxycyclobutyl)-4- methyl-1-phenyl-1H-pyrazol-5-ylcarbamate MS (apci) m/z = 364.2 (M + H). 210

phenyl 3-(2- hydroxyethyl)-4-methyl- 1-phenyl-1H-pyrazol-5- ylcarbamateMS (apci) m/z = 338.1 (M + H). 211

ethyl 4-methyl-5- (phenoxycarbonylamino)- 1-phenyl-1H-pyrazole-3-carboxylate MS (apci) m/z = 366.1 (M + H). 212

phenyl 4-methyl-3- (methylcarbamoyl)-1- phenyl-1H-pyrazol-5- ylcarbamateMS (apci) m/z = 351.1 (M + H). 213

phenyl 3-carbamoyl-4- methyl-1-phenyl-1H- pyrazol-5-ylcarbamate MS(apci) m/z = 337.1 (M + H). 214

phenyl (4-methyl-3-(5- methyl-1,3,4-oxadiazol- 2-yl)-1-phenyl-1H-pyrazol-5-yl)carbamate MS (apci) m/z = 376.1 (M + H). 215

phenyl 4-methyl-3-(3- methyl-1,2,4-oxadiazol- 5-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate MS (apci) m/z = 376.1 (M + H). 216

phenyl 4-methyl-1- phenyl-3-(3- (trifluoromethyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-5-ylcarbamate MS (apci) m/z = 430.1 (M + H).217

tert-butyl 4-(5- ((phenoxycarbonyl)amino)- 1-phenyl-1H-pyrazol-3-yl)piperidine-1- carboxylate MS (apci) m/z = 463.3 (M + H) 218

phenyl (4-methyl-1- phenyl-3-(tetrahydro- 2H-pyran-4-yl)-1H-pyrazol-5-yl)carbamate MS (apci) m/z = 378.2 (M + H) 219

phenyl (3-(3,5- dimethylisoxazol-4-yl)- 1-phenyl-1H-pyrazol-5-yl)carbamate ¹H NMR (CDCl₃) δ 7.56- 7.64 (m, 4H), 7.48-7.52 (m, 1H),7.40 (t, 2H), 7.26 (t, 2H), 7.16 (br s, 2H), 6.71 (br s, 1H), 2.60 (s,3H) 2.46 (s, 3H) 220

phenyl (4-methyl-3-(5- methylisoxazol-3-yl)-1- phenyl-1H-pyrazol-5-yl)carbamate ¹H NMR (CDCl₃) δ 7.54 (d, 2H), 7.49 (t, 2H), 7.41 (t, 1H),7.33 (br s, 2H), 7.20 (br s, 1H), 7.08 (br s, 1H), 6.74 (br s, 1H), 6.66(br s, 1H), 6.48 (s, 1H), 2.45 (s, 3H) 2.34 (s, 3H) 221

phenyl (3-(4- cyanotetrahydro-2H- pyran-4-yl)-4-methyl-1-phenyl-1H-pyrazol-5- yl)carbamate ¹H NMR (CDCl₃) δ 7.06- 7.56 (m, 9H),6.75 (br s, 1H), 6.51 (s, 1H), 4.04 (d, 2H) 3.89 (t, 2H), 2.20- 2.39 (m,4H), 2.28 (s, 3H) 222

(R)-tert-butyl 2-(4- methyl-5-((phenoxy- carbonyl)amino)-1-phenyl-1H-pyrazol-3- yl)pyrrolidine-1- carboxylate MS (apci) m/z = 463.2(M + H) 223

(S)-tert-butyl 2-(4- methyl-5-((phenoxy- carbonyl)amino)-1-phenyl-1H-pyrazol-3- yl)pyrrolidine-1- carboxylate MS (apci) m/z = 463.2(M + H) 224

(R)-tert-butyl 2-(5- ((phenoxycarbonyl) amino)-1-phenyl-1H- pyrazol-3-yl)pyrrolidine-1- carboxylate MS (apci) m/z = 449.2 (M + H) 225

(S)-tert-butyl 2-(5- ((phenoxycarbonyl) amino)-1-phenyl-1H- pyrazol-3-yl)pyrrolidine-1- carboxylate MS (apci) m/z = 449.2 (M + H) 226

tert-butyl 4-((5- ((phenoxycarbonyl) amino)-1-phenyl-1H- pyrazol-3-yl)methoxy)piperidine- 1-carboxylate MS (apci) m/z = 493.2 (M + H) 227

phenyl (3- (hydroxymethyl)-1- phenyl-1H-pyrazol-5- yl)carbamate MS(apci) m/z = 310.1 (M + H)

Intermediate 228

tert-butyl4-((4-chloro-5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yl)methoxy)piperidine-1-carboxylate

To a suspension of tert-butyl4-((5-(phenoxycarbonylamino)-1-phenyl-1H-pyrazol-3-yl)methoxy)piperidine-1-carboxylate(Intermediate 226), 98.5 mg, 0.200 mmol) in DCM (2.0 mL) was addedpyridinium 4-methylbenzenesulfonate (PPTS) (5.03 mg, 0.020 mmol) andN-chlorosuccinimide (40.1 mg, 0.300 mmol). The resulting solution wasstirred at ambient temperature for 8 days. The mixture was diluted withwater and CH₂Cl₂, the organic layer was separated and the aqueous wasextracted with CH₂Cl₂ (2×). The combined organic fractions were driedover MgSO₄, filtered and concentrated. The residue was purified bysilica chromatography using 30-40% EtOAc/hexanes gradient elution toafford the title compound as an orange oil (73.5 mg, 70% yield). MS(apci) m/z=527.2 (M+H).

Intermediate 229

Phenyl (4-chloro-3-(hydroxymethyl)-1-phenyl-1H-pyrazol-5-yl)carbamate

Prepared from phenyl 3-(hydroxymethyl)-1-phenyl-1H-pyrazol-5-ylcarbamate(Intermediate 227) using the procedure outlined for the preparation oftert-butyl4-((4-chloro-5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yl)methoxy)piperidine-1-carboxylate(Intermediate 228). In this instance, the compound was isolated a whitesolid (108 mg, 28%). MS (apci) m/z=344.0 (M+H).

Intermediate 230

Phenyl (4-bromo-3-(hydroxymethyl)-1-phenyl-1H-pyrazol-5-yl)carbamate

To a suspension of phenyl3-(hydroxymethyl)-1-phenyl-1H-pyrazol-5-ylcarbamate (Intermediate 227,100 mg, 0.323 mmol) in CH₂Cl₂ (1.6 mL) was added pyridinium4-methylbenzenesulfonate (PPTS) (8.12 mg, 0.0323 mmol) andN-bromosuccinimide (86.3 mg, 0.485 mmol). The reaction mixture wasstirred for 16 hours at ambient temperature. The resulting suspensionwas filtered and the collected solid washed briefly with CH₂Cl₂ anddried in vacuum to afford the title compound a white solid (48.5 mg,39%). MS (apci) m/z=388.0 (M+H).

The following pyrazole intermediates were made according to the methodsdescribed for the preparation of Intermediate 228, 229 or 230.

MS (apci) Intermediate Structure Name m/z 231

phenyl (4-chloro-3- (methoxymethyl)-1-phenyl- 1H-pyrazol-5-yl)carbamate358.1 (M + H) 232

phenyl (4-bromo-3- (methoxymethyl)-1-phenyl- 1H-pyrazol-5-yl)carbamate402.2 (M + H) 233

phenyl (4-chloro-3-(1,1- difluoro-2-hydroxyethyl)-1-phenyl-1H-pyrazol-5- yl)carbamate 394.1 (M + H) 234

phenyl (4-chloro-3-(2- hydroxy-2-methylpropyl)-1- phenyl-1H-pyrazol-5-yl)carbamate 386.1 (M + H) 235

(S)-phenyl (4-chloro-3-(2- hydroxypropyl)-1-phenyl-1H-pyrazol-5-yl)carbamate 372.1 (M + H) 236

(R)-phenyl (4-chloro-3-(2- hydroxypropyl)-1-phenyl-1H-pyrazol-5-yl)carbamate 372.1 (M + H) 237

(R)-phenyl (4-bromo-3-(2- hydroxypropyl)-1-phenyl-1H-pyrazol-5-yl)carbamate 416.0 (M + H) 238

phenyl (4-chloro-3-(3- hydroxycyclobutyl)-1-phenyl-1H-pyrazol-5-yl)carbamate 384.1 (M + H) 239

phenyl 4-chloro-3-(3-methyl- 1,2,4-oxadiazol-5-yl)-1-phenyl-1H-pyrazol-5- ylcarbamate 396.0 (M + H) 240

phenyl (4-chloro-3-(2- hydroxy-2-methylpropoxy)-1- phenyl-1H-pyrazol-5-yl)carbamate 446.1 (M + H) 241

phenyl (4-chloro-3-(2- hydroxy-2-methylpropoxy)-1- phenyl-1H-pyrazol-5-yl)carbamate 388.1 (M + H) 242

phenyl (4-bromo-3-(2- hydroxy-2-methylpropoxy)-1- phenyl-1H-pyrazol-5-yl)carbamate 433.0 (M + H) 243

ethyl 4-bromo-5- ((phenoxycarbonyl)amino)-1- phenyl-1H-pyrazole-3-carboxylate 430.0 (M + H)

Intermediate 244

2-phenylpyrazolo[1,5-a]pyridin-3-amine Step A: Ethyl2-phenylpyrazolo[1,5-a]pyridine-3-carboxylate

To a solution of 1-aminopyridinium iodide (2.22 g, 10.0 mmol) in DMF (20mL) was added K₂CO₃ (1.93 g, 14.0 mmol) and ethyl 3-phenylpropiolate(3.30 mL, 20.0 mmol). The mixture was stirred at ambient temperature for18 hours and was poured chilled water (100 mL). The mixture was stirredfor 30 minutes and was filtered through packed Celite®, rinsing withEtOAc and H₂O. The organic layer was removed and was washed with H₂O(4×), dried with over MgSO₄, filtered and concentrated. The residualdark red-orange oil was purified by silica chromatography using a 10-50%EtOAc/hexanes gradient elution to furnish the title compound as a yellowsolid (1.75 g, 65.7% yield). MS (apci) m/z=267.0 (M+H).

Step B: 2-phenylpyrazolo[1,5-a]pyridine-3-carboxylic acid hydrochloride

To solution of ethyl 2-phenylpyrazolo[1,5-a]pyridine-3-carboxylate (1.72g, 6.46 mmol) in EtOH (10 mL) was added 2M NaOH (16.1 mL, 32.3 mmol) andthe reaction mixture was heated at reflux for 7 hours. The reactionmixture was cooled to ambient temperature and was cooled in an ice bath.The mixture was acidified with concentrated HCl and the resultingsuspension was collected via vacuum filtration. The product cake waswashed with water and dried in vacuum to afford the title compound as agold solid (1.69 g, 95.2% yield). MS (apci) m/z=195.2 ((M+H)—CO₂).

Step C: 2-phenylpyrazolo[1,5-a]pyridine

A mixture of 2-phenylpyrazolo[1,5-a]pyridine-3-carboxylic acidhydrochloride (1.00 g, 3.64 mmol) in polyphosphoric acid (41.6 m, 364mmol) was heated at 80° C. for 17 hours. The resulting gelatinousmixture was cooled to ambient temperature and ice water was added (150mL). The mixture was stirred until a granular suspension began to form.The suspension was transferred to water (350 mL) and the mixture stirreduntil a fine granular suspension resulted. The solid was collected viavacuum filtration, washed with water and dried in vacuum to afford thetitle compound as an orange solid (0.84 g, 118%) that was used directlyin the next step. MS (apci) m/z=195.2 (M+H).

Step D: 3-nitroso-2-phenylpyrazolo[1,5-a]pyridine

To a solution of 2-phenylpyrazolo[1,5-a]pyridine (0.84 g, 2.85 mmol) inacetic acid (2.85 mL, 51.4 mmol) was added NaNO₂ (0.295 g, 4.28 mmol) inwater (1.43 mL) dropwise over 10 minutes (vigorous bubbling observed).The mixture was stirred for 20 minutes and was quenched with ice. Theresulting suspension was warmed to ambient temperature and the solidcollected via vacuum filtration. The collected solid was washed withwater and dried in vacuum to provide the title compound as a dark greensolid (0.380 g, 59.6%). MS (apci) m/z=224.1 (M+H).

Step E: 2-phenylpyrazolo[1,5-a]pyridin-3-amine

To a mixture of 3-nitroso-2-phenylpyrazolo[1,5-a]pyridine (0.380 g, 1.70mmol) and Zn dust (0.557 g, 8.51 mmol) in EtOH (3.81 mL) was addedconcentrated HCl (0.156 mL, 1.87 mmol). The mixture was heated at refluxfor 3 hours and was cooled to ambient temperature. The mixture wasdiluted with MeOH, filtered and the Zn cake washed with MeOH. Thecombined filtrate and washes were concentrated and the residue waspartitioned into in water and DCM. The organic layer was removed and theaqueous portion was treated with saturated NaHCO₃ to achieve pH=10. Themixture was extracted with DCM (3×) and the combined extracts werewashed with saturated NaCl, dried over MgSO₄, filtered and concentrated.The residue was dried in vacuum to furnish the title compound as brownsolid (0.304 g, 85.5% yield). MS (apci) m/z=210.1 (M+H). ¹H NMR (CDCl₃)δ 8.31 (d, 1H), 7.91 (d, 2H), 7.49 (t, 2H), 7.38 (t, 2H), 6.96 (dd, 1H),6.64 (t, 1H), 3.21 (br s, 2H).

Intermediate 245

5-methyl-3-phenyl-1-(pyrazin-2-yl)-1H-pyrazol-4-amine Step A:2-(5-methyl-4-nitroso-3-phenyl-1H-pyrazol-1-yl)pyrazine

To a solution of 2-hydrazinylpyrazine (0.485 g, 4.40 mmol) in HOAc (6mL) was added (2-(hydroxyimino)-1-phenylbutane-1,3-dione (0.765 g, 4.00mmol) in small portions over 2 minutes. The mixture was stirred for 5minutes and the resulting light orange suspension was stirred at 60° C.for 6 hours. EtOH (1 mL) was added and the mixture was heated at 60° C.for an additional 6 hours. The resulting dark green suspension wascooled to ambient temperature and the mixture was diluted with H₂O (30mL). The green suspension was stirred for 1 hour and the solid wascollected via vacuum filtration. The collected solid was washed with H₂Oand dried in vacuum. The solid was suspended in EtOH (25 mL) andconcentrated HCl (500 μL) was added. The mixture was heated at refluxfor 20 hours, cooled to ambient temperature and diluted with chilled H₂O(75 mL). The mixture was treated with 1M NaOH to pH=7 and was extractedwith Et₂O (3×). The combined extracts were washed with saturated NaCland dried over MgSO₄. The dried solution was filtered through packedCelite® and concentrated. The residual green-yellow solid was purifiedon a SiO₂ column using step gradient elution (25% CH₂Cl₂, 50%EtOAc/hexanes) to furnish the title compound as a turquoise solid (325mg, 31%). MS (apci) m/z=266.1 (M+H).

Step B: 5-methyl-3-phenyl-1-(pyrazin-2-yl)-1H-pyrazol-4-amine

To a mixture of 2-(5-methyl-4-nitroso-3-phenyl-1H-pyrazol-1-yl)pyrazine(325 mg, 1.04 mmol) and Zn dust (340 mg, 5.21 mmol) in EtOH (10 mL) wasadded concentrated HCl (95.5 μL, 1.15 mmol). The mixture was stirred atambient temperature for 17 hours, then at 65° C. for 3 hours. Themixture was cooled to ambient temperature and was filtered throughpacked Celite® eluting with MeOH. The eluent was concentrated, and theresidue was treated with H₂O and mixed. The resulting orange suspensiontreated with 2M HCl to pH=1 and the mixture was extracted with Et₂O(3×). The aqueous portion was treated with 2M NaOH to pH=8 and extractedwith EtOAc (3×). The combined EtOAc extracts were washed with saturatedNaCl and dried over MgSO₄/activated carbon. The solution was elutedthrough a SiO₂ plug eluting with EtOAc. The eluent was concentrated togive the title compound as a light yellow wax (33 mg, 13%). MS (esi)m/z=252.2 (M+H).

Intermediate 246

1,5-dimethyl-3-phenyl-1H-pyrazol-4-amine Step A:1,5-dimethyl-4-nitroso-3-phenyl-1H-pyrazole

To a solution of methylhydrazine (0.484 g, 10.5 mmol) in HOAc (10 mL)was added 2-(hydroxyimino)-1-phenylbutane-1,3-dione (2.01 g, 10.5 mmol)in small portions over 5 minutes. The reaction mixture was heated at 60°C. for 1 hour and was cooled to ambient temperature. Et₂O (50 mL) andH₂O (10 mL) were added to the mixture followed by slow addition ofsaturated Na₂CO₃ until pH=8 was obtained. The organic layer was removedand the aqueous layer was extracted with Et₂O (2×). The combined organicfractions were dried over Na₂SO₄, filtered and concentrated. The residuewas purified by silica gel chromatography (1:5 EtOAc/hexanes) to givethe title compound as a green solid (1.32 g, 63%). MS (apci) m/z=202.1(M+H).

Step B: 1,5-dimethyl-3-phenyl-1H-pyrazol-4-amine

To a solution of 1,5-dimethyl-4-nitroso-3-phenyl-1H-pyrazole (1.32 g,6.60 mmol) in MeOH (50 mL) was added Pd(OH)₂ on carbon (200 mg, 20 wt %,0.286 mmol) and the reaction mixture was shaken under 50 psi of H₂ for 3hours at ambient temperature. The reaction mixture was evacuated, purgedwith N₂ filtered through a pad of Celite® with MeOH elution. The eluentwas concentrated and the residue dried in vacuum to provide the titlecompound as a tan solid (1.23 g, 100%). MS (apci) m/z=188.1 (M+H).

Intermediate 247

1-isopropyl-5-methyl-3-phenyl-1H-pyrazol-4-amine

The title compound was prepared according to the method described forIntermediate 246, using isopropylhydrazine hydrochloride in place ofmethylhydrazine in Step A to provide 620 mg (57%) of the title compoundover 2 steps. MS (apci) m/z=216.1 (M+H).

Intermediate 248

5-methyl-3-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-amine Step A:5-methyl-4-nitroso-3-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole

The title compound was prepared using (2,2,2-trifluoroethyl)hydrazine inplace of methylhydrazine in Step A of the procedure described for thepreparation of 1,5-dimethyl-3-phenyl-1H-pyrazol-4-amine (Intermediate246). The compound was isolated as a green solid (999 mg, 71%). ¹H NMR(CDCl₃) δ 7.60-7.73 (m, 5H), 4.70 (q, 2H), 2.27 (t, 3H).

Step B: 5-methyl-3-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-amine

To a mixture of5-methyl-4-nitroso-3-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole (50 mg,0.186 mmol) and Zn dust (60.7 mg, 0.929 mmol) in EtOH (0.4 mL) was addedconcentrated HCl (17.0 μL, 0.204 mmol) and the mixture was heated atreflux for 3 hours. The mixture was cooled to ambient temperature andwas diluted with MeOH and filtered. The filtrate was concentrated andthe residue was diluted in water. The aqueous mixture was treated withsaturated NaHCO₃ until pH=10 was achieved. The mixture was extractedwith DCM (3×) and the combined extracts were dried over Na₂SO₄, filteredand concentrated afford the title compound as a yellow oil (47.1 mg,99.4% yield). MS (apci) m/z=256.1 (M+H).

Intermediate 249

1-ethyl-5-methyl-3-phenyl-1H-pyrazol-4-amine Step A:1-ethyl-5-methyl-4-nitroso-3-phenyl-1H-pyrazole

The title compound was prepared according to the procedure described forthe preparation of Intermediate 246, using ethylhydrazine oxalate inplace of methylhydrazine in Step A.1-Ethyl-5-methyl-4-nitroso-3-phenyl-1H-pyrazole was isolated as a greenoil (288 mg, 26%). ¹H NMR (CDCl₃) δ 8.19 (d, 2H), 7.46-7.50 (m, 3H),4.15 (q, 2H), 2.43 (s, 3H), 1.50 (t, 3H). The minor regioisomer,1-ethyl-3-methyl-4-nitroso-5-phenyl-1H-pyrazole, was also obtained as ablue-green solid (165 mg, 15%). ¹H NMR (CDCl₃) δ 7.71 (dd, 2H), 7.59 (m,3H), 4.17 (q, 2H), 2.28 (s, 3H), 1.51 (t, 3H).

Step B: 1-ethyl-5-methyl-3-phenyl-1H-pyrazol-4-amine

Prepared according to the procedure described for the preparation ofIntermediate 248, using 1-ethyl-5-methyl-4-nitroso-3-phenyl-1H-pyrazolein Step B. the title compound was isolated as a light purple solid (281mg, 104%). MS (apci) m/z=202.1 (M+H).

Intermediate 250

1-ethyl-3-methyl-5-phenyl-1H-pyrazol-4-amine

Prepared according to the procedure described for the preparation ofIntermediate 249, using 1-ethyl-3-methyl-4-nitroso-5-phenyl-1H-pyrazolein Step A. The title compound was prepared according to Step B. Thecompound was isolated as a colorless oil (82.4 mg, 52.5%) afterpurification by reverse-phase chromatography. MS (apci) m/z=202.1 (M+H).

Intermediate 251

1-methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-amine Step A:4,4,4-trifluoro-2-(hydroxyimino)-1-phenylbutane-1,3-dione

A solution of 4,4,4-trifluoro-1-phenylbutane-1,3-dione (5.00 g, 23.1mmol) in HOAc (46.3 mL) was chilled to 10° C. and sodium nitrite (1.84g, 26.6 mmol) in water (6.0 mL) was added. The mixture was stirred atambient temperature for 90 minutes and was diluted with H₂O (150 mL).The mixture was extracted with Et₂O (3×) and the combined organicfractions were carefully washed with saturated NaHCO₃ until pH=9. TheEt₂O solution was washed with H₂O and saturated NaCl and was dried overMgSO₄. The dried solution was filtered and concentrated to afford thetitle compound as a yellow foam (4.21 g, 74.2% yield). MS (apci)m/z=244.1 (M−H).

Step B: 4-nitroso-3-phenyl-5-(trifluoromethyl)-1H-pyrazole

A solution of hydrazine monohydrate (0.204 g, 4.08 mmol) in EtOH (5 mL)was cooled to 0° C. and4,4,4-trifluoro-2-(hydroxyimino)-1-phenylbutane-1,3-dione (1.00 g, 4.08mmol) in EtOH (15 mL) was added. The reaction mixture was stirred atambient temperature for 3 hours, excess powdered MgSO₄ was added and themixture was heated at 60° C. for 16 hours. The mixture was cooled toambient temperature, filtered and concentrated to afford the crude titlecompound as a green solid (78.7 mg, 8.0%) that was taken directly to thenext step. MS (apci) m/z=240.0 (M−H).

Step C: 1-methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-amine

To a solution of 4-nitroso-3-phenyl-5-(trifluoromethyl)-1H-pyrazole(78.7 mg, 0.326 mmol) in DMF (1.6 mL) was added NaH (14.4 mg, 0.359mmol) and the mixture was stirred at ambient temperature for 30 minutes.The mixture was treated with methyl iodide (40.6 μL, 0.653 mmol) andstirred for 17 hours. The reaction mixture was directly purified byreverse phase HPLC using 20-100% acetonitrile/water gradient elution toprovide a light blue solid (40.2 mg). The solid was dissolved in EtOH(0.35 mL) and was subjected to the reduction procedure described in StepB of the preparation of5-methyl-3-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-amine(Intermediate 248). The title compound was obtained as white solid (25.1mg, 66.1%).

Intermediate 252

1-methyl-3-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-amine Step A:1-methyl-4-nitroso-3-phenyl-5-(trifluoromethyl)-1H-pyrazole

To a solution of methylhydrazine (0.214 mL, 4.08 mmol) in EtOH (20 mL)was added 4,4,4-trifluoro-2-(hydroxyimino)-1-phenylbutane-1,3-dione(Intermediate 251, Step A; 1.00 g, 4.079 mmol). The reaction mixture wasstirred at ambient temperature for 1 hour and excess MgSO₄ was added.The mixture was stirred at 60° C. for 48 hours and was cooled to ambienttemperature. The mixture was filtered and the filtrate concentrated to agreen residue. The residue was purified by silica gel chromatographyusing a 10-30% EtOAc/hexanes gradient for elution to provide the titlecompound as a green solid (482 mg, 46%). ¹H NMR (CDCl₃) δ 7.89 (d, 2H),7.45-7.52 (m, 3H), 4.15 (s, 3H).

Step B: 1-methyl-3-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-amine

Prepared from1-methyl-4-nitroso-3-phenyl-5-(trifluoromethyl)-1H-pyrazole according tothe method described for the preparation of Intermediate 248, Step B.The title compound was obtained as white solid (309 mg, 68%). ¹H NMR(CDCl₃) δ 7.65 (d, 2H), 7.45 (t, 2H), 7.35 (t, 1H), 3.93 (s, 3H), 3.52(br s, 2H).

Preparation U-1

1-(3-(2-(tert-butyldimethylsilylox)ethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the method of Example 1, replacingtrans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride(Preparation B) with(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation F) and using the Intermediate P203. MS (apci) m/z=630.1(M+H).

Preparation U-2

1-(3-((S)-2-(tert-butyldimethylsilyloxy)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the method of Example 1, replacingtrans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride(Preparation B) with(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation F) and using Intermediate P211. MS (apci) m/z=644.4 (M+H).

SYNTHETIC EXAMPLES Example 1

1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)ureaStep A: Preparation of phenyl3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate

To a solution of 3-tert-butyl-1-phenyl-1H-pyrazol-5-amine (Table 1;200.0 mg, 0.9290 mmol) in EtOAc (10 mL) was added 2 M aqueous NaOH(0.9290 mL, 1.858 mmol) followed by phenyl chloroformate (0.1632 mL,1.301 mmol). The reaction was stirred at ambient temperature for 1 hourand then the phases were separated. The organic phase was washed withH₂O (10 mL), brine (10 mL), dried with MgSO₄, filtered and concentratedto yield the product as a brown crystalline solid (320 mg, 103% yield).MS (apci) m/z=336.1 (M+H).

Step B: Preparation of1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea

To a solution of trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-aminedihydrochloride (Preparation B, 30.0 mg, 0.102 mmol) and DIEA (0.0535mL, 0.307 mmol) in DMA (1 mL) was added phenyl3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate (34.3 mg, 0.102 mmol),and the reaction mixture as stirred at ambient temperature for 1 hour.The reaction mixture was directly purified by reverse-phase columnchromatography, eluting with 5-60% acetonitrile/water to yield theproduct as a tan solid (38 mg, 81% yield). MS (apci) m/z=462.2 (M+H).

The compounds of Table 4 were prepared according to the method ofExample 1 using the appropriate starting materials.

TABLE 4 Ex. # Structure Name Data 2

1-(3-tert-butyl-1-p-tolyl-1H- pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)urea hydrochloride MS (apci) m/z= 476.3 (M + H). 3

trans-1-(4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6- tetrahydrocyclopenta[c]pyrazol- 3-yl)urea MS(apci) m/z = 482.4 (M + H). 4

trans-1-(4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-isopropyl-1-phenyl- 1H-pyrazol-5-yl)urea MS (apci) m/z = 484.7(M + H). 5

1-(3-tert-butyl-1-methyl-1H- pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)urea MS (apci) m/z = 400.2 (M +H). 6

1-(1,3-dimethyl-1H-pyrazol-5- yl)-3-(trans-1-(2- methoxyethyl)-4-phenylpyrrolidin-3-yl)urea MS (apci) m/z = 358.1 (M + H). 7

1-(3-tert-butyl-1-(pyridin-3- yl)-1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)urea MS (apci) m/z =463.2 (M + H). 8

1-(3-tert-butyl-1-(4- fluorophenyl)-1H-pyrazol-5- yl)-3-(trans-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)urea MS (apci) m/z = 480.2 (M +H). 9

1-(3-cyclopropyl-1-phenyl- 1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)urea MS (apci) m/z = 446.2(M + H). 10

1-(1,3-diphenyl-1H-pyrazol- 5-yl)-3-(trans-1-(2- methoxyethyl)-4-phenylpyrrolidin-3-yl)urea MS (apci) m/z = 482.2 (M + H). 11

1-(trans-1-(2-methoxyethyl)- 4-phenylpyrrolidin-3-yl)-3-(3-methyl-1-phenyl-1H- pyrazol-5-yl)urea MS (apci) m/z = 420.1 (M + H).12

1-(3-isopropyl-1-phenyl-1H- pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)urea MS (apci) m/z = 448.2 (M +H). 13

1-(trans-1-(2-methoxyethyl)- 4-phenylpyrrolidin-3-yl)-3-(1-methyl-3-phenyl-1H- pyrazol-5-yl)urea MS (apci) m/z = 420.1 (M + H).14

1-(trans-1-(2-methoxyethyl)- 4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6- tetrahydrocyclopenta[c]pyrazol- 3-yl)urea MS (apci)m/z = 446.2 (M + H). 15

1-(trans-1-(2-methoxyethyl)- 4-phenylpyrrolidin-3-yl)-3-(1-phenyl-1H-pyrazol-5- yl)urea MS (apci) m/z = 406.1 (M + H). 16

1-(3-tert-butyl-1-(2- fluorophenyl)-1H-pyrazol-5- yl)-3-(trans-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)urea MS (apci) m/z = 480.1 (M +H). 17

1-(3-tert-butyl-1-(3- fluorophenyl)-1H-pyrazol-5- yl)-3-(trans-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)urea MS (apci) m/z = 480.1 (M +H). 18

1-(3,4-dimethyl-1-phenyl-1H- pyrazol-5-yl)-3-(trans-1-(2-Methoxyethyl)-4- phenylpyrrolidin-3-yl)urea MS (apci) m/z = 434.2 (M +H). 19

1-(trans-1-(2-methoxyethyl)- 4-phenylpyrrolidin-3-yl)-3-(2-(pyridin-3-yl)-2,4,5,6- tetrahydrocyclopenta[c]pyrazol- 3-yl)urea MS(apci) m/z = 447.2 (M + H).

Example 20

1-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(1-methyl-1H-pyrazol-5-yl)ureaStep A: Preparation of 4-nitrophenyltrans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-ylcarbamate

To a suspension of trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-aminedihydrochloride (Preparation B; 0.180 g, 0.614 mmol) in DCM (3 mL) at 0°C. was added triethylamine (0.428 mL, 3.07 mmol) followed by dropwiseaddition of a solution of 4-nitrophenyl carbonochloridate (0.136 g,0.675 mmol) in DCM (0.5 mL). The ice bath was removed and the reactionmixture stirred at ambient temperature for 1 hour. The mixture wasdiluted in saturated NaHCO₃ (30 mL) and extracted with DCM (3×20 mL).The combined organic layers were washed with brine (20 mL), dried withMgSO₄, filtered and concentrated in vacuo to yield the crudeintermediate, which was used in the next step without purification. MS(apci) m/z=386.2 (M+H).

Step B: Preparation of1-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(1-methyl-1H-pyrazol-5-yl)urea

To a solution of 4-nitrophenyltrans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-ylcarbamate (80 mg, 0.21mmol) in DCE (1 mL) was added 1-methyl-1H-pyrazol-5-amine (Table 1; 24mg, 0.25 mmol) followed by DIEA (0.15 mL, 0.83 mmol). The mixture washeated at 55° C. for 18 hours, then diluted with 1 mL of DCM, washedwith saturated bicarbonate (2×1 mL) and concentrated in vacuo. The cruderesidue was purified by reverse-phase column chromatography eluting with5-45% acetonitrile/water to afford the title product (10 mg, 14% yield).MS (apci) m/z=344.2 (M+H).

Example 21

1-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)thiourea

To a CHCl₃ (0.5 mL) suspension of2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine (Table 1; 45.2mg, 0.227 mmol) was added di(1H-imidazol-1-yl)methanethione (40.4 mg,0.227 mmol) followed by DIEA (0.158 mL, 0.908 mmol). After stirring atambient temperature for 16 hours,trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine (Preparation B, 50.0mg, 0.227 mmol) was added to the reaction mixture in one portion. After2 hours, the reaction was directly purified by reverse-phase columnchromatography, eluting with 5-68% acetonitrile/water to yield the titleproduct as white solid (70 mg, 67% yield). MS (apci) m/z=462.1 (M+H).

Example 22

1-(2-(3-fluorophenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea

A solution of2-(3-fluorophenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine(Intermediate P3; 25.0 mg, 0.115 mmol) in DCM (575 μL, 0.115 mmol) wastreated with 1,1′-carbonyldiimidazole (18.7 mg, 0.115 mmol) and TEA(32.1 μL, 0.230 mmol). After stirring at ambient temperature for 3hours, trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-aminedihydrochloride (Preparation B, 33.7 mg, 0.115 mmol) was added, followedby TEA (64.2 μL, 0.460 mmol). After stirring at ambient temperature for30 minutes, the crude reaction mixture was directly purified byreverse-phase column chromatography, eluting with 0-100%acetonitrile/water, to afford the title compound as a clear oil (17.6mg, 33.0% yield). MS (apci) m/z=464.1 (M+H).

The compounds of Table 5 were prepared according to the method ofExample 22 using the appropriate starting materials. Conversion time tothe activated intermediate with 1,1′-carbonyldiimidazole varied, and wasmonitored by taking an aliquot and quenching in MeOH. LCMS analysis wasused to monitor complete conversion to the methyl carbamate (30 minutesto 16 hours).

TABLE 5 Ex. # Structure Name Data 23

1-(2-(4-fluorophenyl)-2,4,5,6- tetrahydrocyclopenta[c]pyrazol-3-yl)-3-(trans-1-(2- methoxyethyl)-4- phenylpyrrolidin-3-yl)urea MS(apci) m/z = 464.0 (M + H). 24

1-(3-cyclopentyl-1-phenyl-1H- pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)urea MS (apci) m/z = 474.2 (M +H). 25

1-(1-ethyl-3-phenyl-1H-pyrazol- 5-yl)-3-(trans-1-(2- methoxyethyl)-4-phenylpyrrolidin-3-yl)urea MS (apci) m/z = 434.2 (M + H). 26

1-(trans-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)-3-(2-phenyl-4,5,6,7-tetrahydro-2H- indazol-3-yl)urea MS (apci) m/z = 460.2(M + H). 27

1-(trans-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)-3-(2-methyl-2,4,5,6- tetrahydrocyclopenta[c]pyrazol- 3-yl)urea MS (apci) m/z= 384.2 (M + H). 28

1-(1,3-dimethyl-4-phenyl-1H- pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)urea MS (apci) m/z = 434.2 (M +H). 29

1-(3-tert-butyl-1-o-tolyl-1H- pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)urea MS (apci) m/z = 476.1 (M +H). 30

1-(3-tert-butyl-1-m-tolyl-1H- pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)urea MS (apci) m/z = 476.2 (M +H). 31

1-(trans-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)-3-(1-methyl-4-phenyl-1H-pyrazol- 5-yl)urea MS (apci) m/z = 420.2 (M + H). 32

1-(4-cyano-3-methyl-1-phenyl- 1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)urea MS (apci) m/z = 445.1(M + H). 33

1-(trans-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)-3-(2-(1-methyl-1H-pyrazol-4-yl)- 2,4,5,6- tetrahydrocyclopenta[c]pyrazol-3-yl)urea MS (apci) m/z = 450.1 (M + H). 34

1-(3-tert-butyl-1-(tetrahyro- 2H-pyran-4-yl)-1H-pyrazol-5-yl)-3-(trans-1-(2- methoxyethyl)-4- phenylpyrrolidin-3-yl)urea MS (apci)m/z = 470.2 (M + H). 35

1-(trans-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)-3-(2-(pyridin-2-yl)-2,4,5,6- tetrahydrocyclopenta[c]pyrazol- 3-yl)urea MS(apci) m/z = 447.0 (M + H). 36

1-(6,6-dimethyl-2-phenyl- 2,4,5,6-tetrahydro-yclopenta[c]pyrazol-3-yl)-3-(trans-1-(2- methoxyethyl)-4-phenyl-pyrrolidin-3-yl)urea MS (apci) m/z = 474.0 (M + H). 37

1-(7,7-dimethyl-2-phenyl- 4,5,6,7-tetrahydro-2H-indazol-3-yl)-3-(trans-1-(2- methoxyethyl)-4- phenylpyrrolidin-3-yl)urea MS(apci) m/z = 488.2 (M + H).

Example 38

1-(trans-1-(2-methoxyethyl)-4-(pyridin-4-yl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureaStep A: Preparation of trans-ethyl1-(2-methoxyethyl)-4-(pyridin-4-yl)pyrrolidine-3-carboxylate

To a solution of (E)-ethyl 3-(pyridin-4-yl)acrylate (200 mg, 1.13 mmol)in DCM (10 mL) cooled to 0° C. were sequentially added TFA (0.017 mL,0.226 mmol) in one portion followed by dropwise addition of2-methoxy-N-(methoxymethyl)-N-((trimethylsilyl) methyl)ethanamine(Preparation C, 278 mg, 1.35 mmol). The reaction was stirred at ambienttemperature for 3 hours. It was quenched with saturated NaHCO₃ (10 mL),the phases were separated and the aqueous layer was extracted with DCM(15 mL). The combined organic phases were dried with MgSO₄, filtered andconcentrated in vacuo. The crude product was purified by silica columnchromatography, eluting with 0 to 5% MeOH/DCM to yield the product as acolorless oil (276 mg, 88% yield). MS (apci) m/z=279.2 (M+H).

Step B: Preparation of lithiumtrans-1-(2-methoxyethyl)-4-(pyridin-4-yl)pyrrolidine-3-carboxylate

To a solution of trans-ethyl1-(2-methoxyethyl)-4-(pyridin-4-yl)pyrrolidine-3-carboxylate (276 mg,0.992 mmol) in THF (6 mL) and MeOH (3 mL) was added 2M aqueous LiOH(0.496 mL, 0.992 mmol). The reaction mixture was stirred at ambienttemperature for 2 hours, and the resulting white precipitate wascollected by vacuum filtration, rinsed with Et₂O, and air dried. Thefiltrate was concentrated to a yellow solid, triturated with MeOH (1mL), filtered, and the white solid rinsed with Et₂O and air dried. Thetwo crops of solids were combined to give the product as a white solid(197 mg, 88% yield). ¹H NMR (d₆-DMSO) δ 8.37-8.39 (m, 2H), 7.26-7.28 (m,2H), 3.36-3.43 (m, 3H), 3.24 (s, 3H), 2.75-2.86 (m, 1H), 2.41-2.68 (m,6H).

Step C: Preparation of benzyltrans-1-(2-methoxyethyl)-4-(pyridin-4-yl)pyrrolidin-3-ylcarbamate

To a suspension of lithiumtrans-1-(2-methoxyethyl)-4-(pyridin-4-yl)pyrrolidine-3-carboxylate (25mg, 0.098 mmol) in toluene (1.8 mL) and DMF (0.2 mL) were sequentiallyadded DIEA (0.034 mL, 0.20 mmol) and diphenylphosphoryl azide (0.029 mL,0.14 mmol). The reaction mixture was stirred at ambient temperature for20 minutes then refluxed for 10 minutes. Benzyl alcohol (100 mg, 0.98mmol) was introduced, and the reaction mixture was refluxed for 17hours. The reaction mixture was directly purified by silica columnchromatography, eluting with 0-10% MeOH/DCM to yield the product as ayellow oil (11 mg, 32% yield). MS (apci) m/z=356.1 (M+H).

Step D: Preparation oftrans-1-(2-methoxyethyl)-4-(pyridin-4-yl)pyrrolidin-3-aminebis(2,2,2-trifluoroacetate)

A solution of benzyltrans-1-(2-methoxyethyl)-4-(pyridin-4-yl)pyrrolidin-3-ylcarbamate (11mg, 0.031 mmol) in TFA (1 mL) was heated in a sealed tube at 60° C. for18 hours. The reaction mixture was transferred with EtOH (5 mL) andconcentrated to give the crude product as a brown oil, which was useddirectly in Step F, assuming quantitative yield. MS (apci) m/z=222.1(M+H).

Step E: Preparation of phenyl2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate

A suspension of 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine(Table 1; 100 mg, 0.50 mmol) in EtOAc (2.0 mL) and 2 M aqueous NaOH(0.50 mL, 1.0 mmol) was treated with phenyl carbonochloridate (0.088 mL,0.70 mmol) dropwise and stirred for 16 hours at ambient temperature. Thereaction mixture was then phase-separated and the organic phase waswashed with water (5 mL) and brine (5 mL), dried over Na₂SO₄, filteredand concentrated in vacuo to afford the product (160 mg, 100% yield). MS(apci) m/z=320.1 (M+H).

Step F: Preparation of1-(trans-1-(2-methoxyethyl)-4-(pyridin-4-yl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

Prepared by the method as described in Example 1, substituting phenyl3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate in Step B with phenyl2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate andsubstituting trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-aminedihydrochloride in Step B withtrans-1-(2-methoxyethyl)-4-(pyridin-4-yl)pyrrolidin-3-aminebis(2,2,2-trifluoroacetate) to provide the final product as a whitesolid (6.0 mg, 42% yield). MS (apci) m/z=447.2 (M+H).

Example 39

trans-1-(4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureaStep A: Preparation of trans-tert-butyl3-(3-fluorophenyl)-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureido)pyrrolidine-1-carboxylate

To a suspension oftrans-1-(tert-butoxycarbonyl)-4-(3-fluorophenyl)pyrrolidine-3-carboxylicacid (purchased from ChemImpex; 100 mg, 0.32 mmol) in anhydrous toluene(2 mL) was added triethylamine (180 μL, 1.29 mmol) followed bydiphenylphosphoryl azide (98 μL, 0.45 mmol). The resulting solution wasstirred at ambient temperature for 1 hour and then at reflux for 1 hour.After cooling, the reaction mixture was treated with2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine (Table 1; 193mg, 0.97 mmol) and stirred at reflux for 15 hours. The cooled mixturewas partitioned between saturated NaHCO₃ (20 mL) and EtOAc (20 mL) andthe aqueous layer was extracted with EtOAc (2×10 mL). The combinedorganic phases were washed with brine (10 mL), dried over Na₂SO₄ andconcentrated in vacuo. The crude material was purified by silica columnchromatography, eluting with 1% MeOH/DCM followed by 5% MeOH/DCM toafford the product as a brown gum. LCMS analysis of the gum indicatedthis to be about a 2:1 mixture of desired product and the symmetricalurea of the 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-aminestarting material (by LCMS). The mixture was taken directly into thenext step. MS (apci) m/z=506.2 (M+H).

Step B: Preparation of1-(trans-4-(3-fluorophenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

To the mixture isolated in Step A (90 mg, 0.18 mmol) in CH₂Cl₂ (8 mL)was added TFA (2 mL). The solution was stirred at ambient temperaturefor 2 hours and then concentrated, and the residue was partitionedbetween 1N NaOH (20 mL) and CH₂Cl₂ (20 mL). The aqueous layer wasextracted with CH₂Cl₂ (2×10 mL), and the combined organic phases werewashed with brine (10 mL), dried over Na₂SO₄ and concentrated to afforda brown gum. Purification by silica column chromatography eluting with2% MeOH/DCM to 10% MeOH/CH₂Cl₂/0.1% 7N NH₃/MeOH afforded the product asa pale yellow solid (31 mg, 43% yield). MS (apci) m/z=406.1 (M+H).

Step C: Preparation oftrans-1-(4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

To a solution of1-(trans-4-(3-fluorophenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea (31 mg, 0.076 mmol) inanhydrous. DMF (1 mL) was added 1-bromo-2-methoxyethane (9.1 μL, 0.09mmol) followed by DIEA (40 μL, 0.23 mmol). The mixture was warmed to 60°C. and stirred for 15 hours. The cooled mixture was partitioned betweensaturated. NaHCO₃ (20 mL) and EtOAc (10 mL) and the aqueous layer wasextracted with EtOAc (2×10 mL). The combined organic phases were washedwith water (5×10 mL) and brine (10 mL) then dried over Na₂SO₄ andconcentrated. The crude material was purified by silica columnchromatography, eluting with 2.5% MeOH/CH₂Cl₂ to afford the product as acolorless glass (14 mg, 40% yield). MS (apci) m/z=464.1 (M+H).

Example 40

trans-1-(-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared using the procedure as described for Example 39, substituting3-isopropyl-1-phenyl-1H-pyrazol-5-amine (Table 1) for2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine in Step A. MS(apci) m/z=466.2 (M+H).

Example 41

trans-1-(4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the procedures described for Example 39,substitutingtrans-1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)pyrrolidine-3-carboxylicacid fortrans-1-(tert-butoxycarbonyl)-4-(3-fluorophenyl)pyrrolidine-3-carboxylicacid in Step A. MS (apci) m/z=466.2 (M+H).

Example 42

trans-1-(4-(3-chlorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the procedures described for Example 40,substitutingtrans-1-(tert-butoxycarbonyl)-4-(3-chlorophenyl)pyrrolidine-3-carboxylicacid fortrans-1-(tert-butoxy-carbonyl)-4-(3-fluorophenyl)pyrrolidine-3-carboxylicacid in Step A. MS (apci) m/z=482.1 (M+H).

Example 43

trans-1-(4-(2-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the procedures described for Example 40,substitutingtrans-1-(tert-butoxycarbonyl)-4-(2-fluorophenyl)pyrrolidine-3-carboxylicacid fortrans-1-(tert-butoxycarbonyl)-4-(3-fluorophenyl)pyrrolidine-3-carboxylicacid in Step A. MS (apci) m/z=466.2 (M+H).

Example 44

trans-1-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)-3-(1-(2-methoxyethyl)-4-(thiophen-2-yl)pyrrolidin-3-yl)urea

Prepared according to the procedures described for Example 40,substitutingtrans-1-(tert-butoxycarbonyl)-4-(thiophen-2-yl)pyrrolidine-3-carboxylicacid fortrans-1-(tert-butoxycarbonyl)-4-(3-fluorophenyl)pyrrolidine-3-carboxylicacid in Step A. MS (apci) m/z=454.1 (M+H).

Example 45

1-((3,4-trans)-4-(2,4-dimethylthiazol-5-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea Step A: Preparation of(E)-methyl 3-(2,4-dimethylthiazol-5-yl)acrylate

A solution of methyl (triphenyl-phosphoranylidene)acetate (2.61 g, 7.80mmol) in CH₂Cl₂ (10 mL) was cooled to 0° C., and then a solution of4-methyl thiazole 4-carboxaldehyde (purchased from Maybridge, 1.00 g,7.08 mmol) in dry CH₂Cl₂ (10 mL) was added dropwise over a period of 15minutes. The reaction was warmed up to ambient temperature and stirredfor 24 hours. After removal of solvent under reduced pressure, theyellowish solid residue obtained was dissolved in CH₂Cl₂ and purified bysilica gel flash chromatography, eluting with 15% EtOAc/hexanes, toprovide the product as a white powder (1.32 g, 94.5% yield). ¹H-NMR (400MHz, DMSO-d⁶) δ 7.73 (d, J=15.62 Hz, 1H), 6.07 (d, J=15.62 Hz, 1H), 3.71(s, 3H, OCH₃), 2.63 (s, 3H, CH₃), 2.42 (s, 3H, CH₃). MS (apci) m/z=198(M+H).

Step B: Preparation of (3,4-trans)-methyl4-(2,4-dimethylthiazol-5-yl)-1-(2-methoxyethyl)pyrrolidine-3-carboxylate

A solution of (E)-methyl 3-(2,4-dimethylthiazol-5-yl)acrylate (200 mg,1.01 mmol) and TFA (7.81 μL, 0.101 mmol) in toluene (15 mL) was cooledin an ice bath, followed by dropwise addition of a solution of2-methoxy-N-(methoxymethyl)-N-((trimethylsilyl)methyl)ethanamine (312mg, 1.52 mmol) in toluene (5 mL). The reaction was warmed up to ambienttemperature and stirred for 3 days. The reaction mixture was washed withsaturated NaHCO₃ (25 mL) and water (2×25 mL), dried with Na₂SO₄,filtered and concentrated in vacuo. The crude material was purified byreverse-phase column chromatography, eluting with 5-50%acetonitrile/water to yield the product as clear oil (43 mg, 14% yield).MS (apci) m/z=299.1 (M+H).

Step C: Preparation of(3,4-trans)-4-(2,4-dimethylthiazol-5-yl)-1-(2-methoxyethyl)pyrrolidine-3-carboxylicacid

To a solution of (3,4-trans)-methyl4-(2,4-dimethylthiazol-5-yl)-1-(2-methoxyethyl)pyrrolidine-3-carboxylate(41 mg, 0.14 mmol) in a mixed solvent system of 2:2:1 THF/MeOH/water(0.7 mL) was added LiOH—H₂O (17 mg, 0.41 mmol), and the mixture wasstirred at ambient temperature overnight. After removal of solvent, thesolid residue was taken up in water (0.2 mL) and acidified with 1 N HCl,until pH 4-5. The mixture was directly purified by reverse-phasechromatography, eluting with 5 to 33% acetonitrile/water to yield theproduct as clear oil (30 mg, 77% yield). MS (apci) m/z=285.1 (M+H).

Step D: Preparation of benzyl(3,4-trans)-4-(2,4-dimethylthiazol-5-yl)-1-(2-methoxyethyl)pyrrolidin-3-ylcarbamate

To a turbid solution of(3,4-trans)-4-(2,4-dimethylthiazol-5-yl)-1-(2-methoxyethyl)pyrrolidine-3-carboxylicacid (25.6 mg, 0.09 mmol) in toluene (0.9 mL) was added TEA (31 μL, 0.22mmol) followed by diphenyl phosphorazidate (27 μL, 0.13 mmol). Themixture was stirred at ambient temperature for 1 hour and then at 100°C. for 1 hour. Benzyl alcohol (19 μL, 0.18 mmol) was added and themixture was heated at 100° C. for 18 hours. After cooling, the mixturewas diluted with EtOAc (2 mL), washed with water (2×1 mL), dried withMgSO₄, filtered and concentrated. The crude residue was purified byreverse-phase column chromatography, eluting with 5 to 60%acetonitrile/water to yield the product as yellowish oil (18 mg, 51%yield). MS (apci) m/z=390.1 (M+H).

Step E: Preparation of(3,4-trans)-4-(2,4-dimethylthiazol-5-yl)-1-(2-methoxyethyl)pyrrolidin-3-aminebis(2,2,2-trifluoroacetate)

A solution of benzyl(3,4-trans)-4-(2,4-dimethylthiazol-5-yl)-1-(2-methoxyethyl)pyrrolidin-3-ylcarbamate(18.0 mg, 0.0462 mmol) in TFA (178 μL, 2.31 mmol) was heated at 60° C.for 18 hours. The reaction mixture was diluted with toluene/EtOH andconcentrated. The crude material was purified by reverse-phase columnchromatography eluting with 5-38% acetonitrile/water to yield theproduct as colorless glassy solid (14 mg, 63% yield). MS (apci)m/z=256.1 (M+H).

Step F: Preparation of1-((3,4-trans)-4-(2,4-dimethylthiazol-5-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

To a clear solution of(3,4-trans)-4-(2,4-dimethylthiazol-5-yl)-1-(2-methoxyethyl)pyrrolidin-3-aminebis(2,2,2-trifluoroacetate) (14 mg, 0.029 mmol) in DMA (0.3 mL) wasadded phenyl2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (11 mg,0.035 mmol). The mixture was cooled in an ice bath, and DIEA (0.020 mL,0.12 mmol) was added. The reaction was warmed up to ambient temperatureand stirred for 5 minutes, then directly purified by reverse-phasechromatography, eluting with 5 to 50% acetonitrile/water to yield thetitle product as white solid (10 mg, 72% yield). MS (apci) m/z=481.2(M+H).

Example 46

1-(trans-1-(2-methoxyethyl)-4-(oxazol-5-yl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea Step A: Preparation of(E)-ethyl 3-(oxazol-5-yl)acrylate

To a suspension of NaH (60% in mineral oil, 227 mg, 5.67 mmol) in THF(40 mL) under N₂ at 0° C. was added dropwise ethyl2-(diethoxyphosphoryl)acetate (1.12 mL, 5.67 mmol). The mixture wasstirred at 0° C. for 30 minutes, and then a solution ofoxazole-5-carbaldehyde (500 mg, 5.15 mmol) in THF (5 mL) was added. Theice bath was removed, and the reaction was stirred at ambienttemperature for 18 hours. The reaction was diluted with H₂O (30 mL) andextracted with EtOAc (50 mL). The organic phase was washed with brine(50 mL), dried with MgSO₄, filtered and concentrated in vacuo. The crudeproduct was purified by silica column chromatography, eluting with 0 to1% MeOH/DCM to yield the product as a pale yellow oil (354 mg, 41.1%yield). ¹H NMR (CDCl₃) δ 7.92 (s, 1H), 7.48 (d, 1H), 7.29 (s, 1H), 6.40(d, 1H), 4.27 (q, 2H), 1.29 (t, 3H).

Step B: Preparation of trans-ethyl1-(2-methoxyethyl)-4-(oxazol-5-yl)pyrrolidine-3-carboxylate

To a solution of (E)-ethyl 3-(oxazol-5-yl)acrylate (354 mg, 2.12 mmol)in DCM (20 mL) at 0° C. were added TFA (0.033 mL, 0.42 mmol), thendropwise2-methoxy-N-(methoxymethyl)-N-((trimethylsilyl)methyl)ethanamine(Preparation C, 522 mg, 2.54 mmol). The ice bath was removed and thereaction stirred at ambient temperature for 18 hours, then the reactionmixture diluted with saturated aqueous NaHCO₃ (20 mL), separated and theaqueous phase extracted with DCM (20 mL). The combined organic phaseswere dried with MgSO₄, filtered and concentrated in vacuo. The crudeproduct was purified by silica column chromatography, eluting with 0-3%MeOH/DCM to yield the product as a pale yellow oil (321 mg, 56.5%yield). MS (apci) m/z=269.2 (M+H).

Step C: Preparation of lithiumtrans-1-(2-methoxyethyl)-4-(oxazol-5-yl)pyrrolidine-3-carboxylate

To a solution of trans-ethyl1-(2-methoxyethyl)-4-(oxazol-5-yl)pyrrolidine-3-carboxylate (321 mg,1.20 mmol) in THF (6 mL) and MeOH (3 mL) was added 2M aqueous LiOH(0.837 mL, 1.67 mmol). The reaction was stirred at ambient temperaturefor 1.5 hours and then concentrated to a yellow sticky solid. The crudeproduct was dissolved in MeOH (10 mL) and concentrated to yield theproduct as a yellow foam (234 mg, 79.4% yield). MS (apci neg) m/z=239.2(M-Li).

Step D: Preparation of benzyltrans-1-(2-methoxyethyl)-4-(oxazol-5-yl)pyrrolidin-3-ylcarbamate

To a solution trans-ethyl1-(2-methoxyethyl)-4-(oxazol-5-yl)pyrrolidine-3-carboxylate (234 mg,0.872 mmol) in DMF (0.8 mL) were added DIEA (0.304 mL, 1.74 mmol) thentoluene (10 mL). Diphenylphosphoryl azide (0.263 mL, 1.22 mmol) wasadded and the reaction was stirred at ambient temperature for 1 hour,then at reflux for 1 hour. Benzyl alcohol (0.903 mL, 8.72 mmol) wasadded and the reaction refluxed for 17 hours. The mixture was cooled anddiluted with H₂O (25 mL) and extracted with DCM (3×20 mL), and thecombined organic phases were washed with brine (25 mL), dried withMgSO₄, filtered, concentrated. The crude product was purified byreverse-phase column chromatography, eluting with 5-70%acetonitrile/water to yield the product as a pale yellow syrup (55 mg,18% yield). MS (apci) m/z=346.1 (M+H).

Step E: Preparation oftrans-1-(2-methoxyethyl)-4-(oxazol-5-yl)pyrrolidin-3-aminebis(2,2,2-trifluoroacetate)

A solution of benzyltrans-1-(2-methoxyethyl)-4-(oxazol-5-yl)pyrrolidin-3-ylcarbamate (55 mg,0.16 mmol) in TFA (2 mL) was heated in a sealed tube at 60° C. for 16hours. The reaction mixture was transferred to a flask containing EtOH(10 mL) and concentrated in vacuo. The crude product was dissolved intoluene (15 mL) and azeotroped three times to yield the crude product asa brown syrup (130 mg, 186% yield). MS (apci) m/z=212.1 (M+H).

Step F: Preparation of1-(trans-1-(2-methoxyethyl)-4-(oxazol-5-yl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

Prepared by the method as described in Example 45, Step F usingtrans-1-(2-methoxyethyl)-4-(oxazol-5-yl)pyrrolidin-3-aminebis(2,2,2-trifluoroacetate) to give the product as a colorless residue(5.0 mg, 18% yield). MS (apci) m/z=437.3 (M+H).

Example 47

1-(trans-4-(isoxazol-5-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

Prepared by the method as described in Example 46, substitutingoxazole-5-carbaldehyde in Step A with isoxazole-5-carbaldehyde. MS(apci) m/z=437.0 (M+H).

Example 48

1-((3,4-trans)-1-(2-methoxyethyl)-4-(3-methoxyphenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureaStep A: Preparation of (3,4-trans)-tert-butyl3-(3-methoxyphenyl)-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureido)pyrrolidine-1-carboxylate

To a mixture of (3,4-trans)-tert-butyl3-amino-4-(3-methoxyphenyl)pyrrolidine-1-carboxylate (30 mg, 0.095 mmol,purchased from BroadPharm) and phenyl2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (37 mg,0.11 mmol) was added DMA (0.5 mL), cooled in an ice bath, then addedDIEA (0.050 mL, 0.29 mmol). The ice bath was removed and the reactionwas stirred at ambient temperature for 2 hours. The reaction mixture wasthen directly purified by reverse-phase chromatography eluting with5-75% acetonitrile/water 5 to 75% to yield the product as white solid(15 mg, 30% yield). MS (apci) m/z=518.0 (M+H).

Step B: Preparation of1-((3,4-trans)-4-(3-methoxyphenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureahydrochloride

A solution of (3,4-trans)-tert-butyl3-(3-methoxyphenyl)-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureido)pyrrolidine-1-carboxylate(15 mg, 0.029 mmol) in 5-6 N HCl in IPA (58 μL, 0.29 mmol) was stirredat ambient temperature for 3 hours, then concentrated in vacuo, treatedwith ether, and dried on high vacuum, yielding the crude product as anoff-white solid. The solid was directly used in the next step withoutfurther purification. MS (apci) m/z=418.1 (M+H).

Step C: Preparation of1-((3,4-trans)-1-(2-methoxyethyl)-4-(3-methoxyphenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

To a DMF (0.3 mL) solution of1-((3,4-trans)-4-(3-methoxyphenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureahydrochloride (13 mg, 0.029 mmol) was addedN-ethyl-N-isopropylpropan-2-amine (16 μL, 0.086 mmol) and1-bromo-2-methoxyethane (4.8 mg, 0.034 mmol), and the reaction wasstirred at ambient temperature for 3 days. The reaction was directlypurified by reverse-phase column chromatography eluting with 5-55%acetonitrile/water, yielding the title product as white solid (10 mg,73% yield). MS (apci) m/z=476.2 (M+H).

Example 49

1-(1-(2-methoxyethyl)-4-(thiazol-2-yl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureaStep A: Preparation oftrans-(1-(2-methoxyethyl)-4-nitropyrrolidin-3-yl)thiazole

PS-DMAP (3.52 g, 5.00 mmol) was added in small portions to a solution ofthiazole-2-carbaldehyde (2.83 g, 25.0 mmol) in acetonitrile (5 mL) andnitromethane (5 mL). The reaction was stirred at ambient temperature for4 hours and acetonitrile (50 mL) was added followed by acetic anhydride(2.59 mL, 27.5 mmol). The reaction was stirred for 1 hour, filtered andconcentrated in vacuo to afford (E)-2-(2-nitrovinyl)thiazole (3.99 g). Aportion of (E)-2-(2-nitrovinyl)thiazole (1.00 g, 6.40 mmol) wasdissolved in DCM (5 mL), cooled to 0° C. and treated with TFA (0.0987mL, 1.28 mmol) followed by2-methoxy-N-(methoxymethyl)-N-((trimethylsilyl) methyl)ethanamine (1.32g, 6.40 mmol) dropwise. The reaction was allowed to warm to ambienttemperature overnight. 1N NaOH (5 mL) was added and the reaction wasextracted with several portions of DCM in a phase separator frit. Thecombined DCM extracts were concentrated to afford the crude titlecompound (1.61 g, 94.1% yield). MS (apci) m/z=258.0 (M+H).

Step B: Preparation oftrans-1-(2-methoxyethyl)-4-(thiazol-2-yl)pyrrolidin-3-amine

trans-1-(2-Methoxyethyl)-4-nitropyrrolidin-3-yl)thiazole (80 mg, 0.31mmol) was dissolved in 1 mL of MeOH and treated with 10% Pd/C (33 mg,0.031 mmol). The reaction mixture was stirred under a hydrogen balloonovernight, filtered through Celite® and concentrated to afford the crudetitle compound (68 mg, 96% yield). MS (apci) m/z=228.1 (M+H).

Step C: Preparation of1-(trans-1-(2-methoxyethyl)-4-(thiazol-2-yl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

trans-1-(2-Methoxy-ethyl)-4-(thiazol-2-yl)pyrrolidin-3-amine (15.0 mg,0.0660 mmol) was dissolved in 1 mL of DCM and treated with DIEA (23.0μL, 0.132 mmol) followed by phenyl2-(cyclohexa-1,3-dienyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate(25.4 mg, 0.0792 mmol). The reaction mixture was stirred at ambienttemperature for 18 hours, concentrated and purified by reverse-phasecolumn chromatography, eluting with 0-50% acetonitrile/water, to affordthe title compound (3.2 mg, 10.7% yield). MS (apci) m/z=453.1 (M+H).

Example 50

1-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

To a DCM (5 mL) solution of(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride(Preparation D; 0.10 g, 0.34 mmol) in DCM (5 mL) at 0° C. wassequentially added phenyl2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (Example38, Step C; 0.13 g, 0.41 mmol) and TEA (0.14 mL, 1.0 mmol). Theresulting mixture was allowed to warmed up to ambient temperature andstirred for 2 hours. It was then treated with EtOAc, washed withsaturated NH₄Cl, saturated NaHCO₃, and brine. The combined organiclayers were dried with MgSO₄, filtered and concentrated. The crudematerial was purified by silica column chromatography, eluting with2-2.5% MeOH/DCM to yield the product (0.11 g, 72% yield). MS (apci)m/z=446.2 (M+H).

Example 51

1-(1,3-diphenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea

1,3-Diphenyl-1H-pyrazol-5-amine (Table 1; 32.0 mg, 0.136 mmol), DIEA(35.6 μL, 0.204 mmol) and 1,1′-carbonyldiimidazole (19.3 mg, 0.119 mmol)were combined in CHCl₃ (0.5 mL) in a sealed vessel and heated at 60° C.for 4 hours. The mixture was cooled to ambient temperature and(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride(Preparation D; 15.0 mg, 0.0681 mmol) was added. After heating at 100°C. for 15 hours, the reaction mixture was concentrated and directlypurified by reverse-phase column chromatography, eluting with 0-70%acetonitrile/water to afford the title compound (5.6 mg, 17% yield). MS(apci) m/z=482.2 (M+H).

Example 52

1-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(1-methyl-3-phenyl-1H-pyrazol-5-yl)urea

To a solution of 1-methyl-3-phenyl-1H-pyrazol-5-amine (Table 1; 49 mg,0.28 mmol) in DCM (2 mL) was added CDI (46 mg, 0.28 mmol) followed byDIEA (200 μL, 1.1 mmol). After 2 hours at ambient temperature, asolution of (3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-aminedihydrochloride (Preparation D, 83 mg, 0.28 mmol) in DCM (0.6 mL) wasadded. The reaction was stirred 15 minutes, then purified directly byreverse-phase column chromatography, eluting with 5-50%acetonitrile/water to afford the title product as a white solid (45 mg,38% yield). MS (apci) m/z=420.1 (M+H).

The compounds of Table 6 were prepared according to the method ofExample 52 using the appropriate starting materials. Conversion time tothe activated intermediate with CDI varied, and was monitored by takingan aliquot and quenching in MeOH. LCMS analysis was used to monitorcomplete conversion to the methyl carbamate (30 minutes to 16 hours).

TABLE 6 Ex. # Structure Name Data 53

1-((3S,4R)-1-(2- methoxyethyl)-4- phenylpyrrolidin-3-yl)-3-(1-phenyl-3-(trifluoromethyl)- 1H-pyrazol-5-yl)urea MS (apci) m/z = 474.2(M + H). 54

1-(1,4-dimethyl-3-phenyl- 1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)urea MS (apci) m/z = 434.1(M + H). 55

1-(3-cyclopropyl-1-methyl- 1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,5-difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3- yl)urea MS(apci) m/z = 420.1 (M + H). 56

1-((3S,4R)-4-(3,5- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-3-(pyridin-2- yl)-1H-pyrazol-5-yl)urea MS (apci) m/z =457.1 (M + H). 57

1-((3S,4R)-4-(3,5- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-3-(pyridin-3- yl)-1H-pyrazol-5-yl)urea MS (apci) m/z =457.1 (M + H). 58

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(1,1′-dimethyl-1H,1′H- 3,4′-bipyrazol-5-yl)urea MS (apci) m/z =460.1 (M + H). 59

1-(3-(3-cyanophenyl)-1- methyl-1H-pyrazol-5-yl)-3- ((3S,4R)-4-(3,4-difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3- yl)urea MS (apci) m/z =481.1 (M + H). 60

1-(3-(4-cyanophenyl)-1- methyl-1H-pyrazol-5-yl)-3- ((3S,4R)-4-(3,4-difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3- yl)urea MS (apci) m/z =481.1 (M + H). 61

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-(imidazo[1,2- a]pyridin-5-yl)-1-methyl-1H- pyrazol-5-yl)urea MS(apci) m/z = 496.1 (M + H). 62

1-(4-chloro-1,3-diphenyl- 1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3- yl)urea MS(apci) m/z = 552.0 (M + H). 63

1-(4-bromo-1,3-diphenyl- 1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3- yl)urea MS(apci) m/z = 596.0 (M + H). 64

1-(4-chloro-3-methyl-1- phenyl-1H-pyrazol-5-yl)-3- ((3S,4R)-4-(3,4-difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3- yl)urea MS (apci) m/z =490.0 (M + H). 65

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(1,3-dimethyl-4- phenyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 470.1(M + H). 66

1-(4-cyano-3-methyl-1- phenyl-1H-pyrazol-5-yl)-3- ((3S,4R)-4-(3,4-difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3- yl)urea MS (apci) m/z =481.1 (M + H). 67

1-(4-chloro-1-methyl-3- phenyl-1H-pyrazol-5-yl)-3- ((3S,4R)-4-(3,4-difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3- yl)urea MS (apci) m/z =490.0 (M + H). 68

1-(4-bromo-1-methyl-3- phenyl-1H-pyrazol-5-yl)-3- ((3S,4R)-4-(3,4-difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3- yl)urea MS (apci) m/z =534.0 (M + H). 69 Example 69 intentionally omitted 70

1-(4-cyano-3-(cyanomethyl)- 1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)urea MS (apci) m/z = 506.0 (M + H). 71

1-(3-(2-cyanopropan-2-yl)-1- phenyl-1H-pyrazol-5-yl)-3- ((3S,4R)-4-(3,4-difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3- yl)urea MS (apci) m/z =509.1 (M + H). 72

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-ethyl-4-methyl-1- phenyl-1H-pyrazol-5-yl)urea MS (apci) m/z =484.1 (M + H). 73

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(1′-methyl-1-phenyl- 1H,1′H-3,4′-bipyrazol-5- yl)urea MS (apci)m/z = 522.1 (M + H). 74

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(oxetan-3- ylmethoxy)-1-phenyl-1H- pyrazol-5-yl)ureaMS (apci) m/z = 542.1 (M + H). 75

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-((3- methyloxetan-3- yl)methoxy)-1-phenyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 556.1 (M + H). 76

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-(((S)-2,2-dimethyl- 1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H- pyrazol-5-yl)urea MS (apci) m/z = 586.1 (M + H).77

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-(((R)-2,2-dimethyl- 1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H- pyrazol-5-yl)urea MS (apci) m/z = 586.2 (M + H).

The compounds of Table 7 were prepared according to the method ofExample 1 replacing the compound of Preparation B with the compound ofPreparation D, E, F, G, H, J or K and using the appropriate pyrazoleintermediate.

TABLE 7 Ex. # Structure Name Data 78

1-(3,4-dimethyl-1-phenyl-1H- pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)urea MS (apci) m/z = 434.1 (M +H). 79

tert-butyl 3-(3-((3S,4R)-1-(2- methoxyethyl)-4-phenylpyrrolidin-3-yl)ureido)-2- phenyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate MS (apci) m/z = 547.1 (M + H). 80

1-(3-isopropyl-4-methyl-1- phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)urea MS (apci) m/z= 462.3 (M + H). 81

1-((3S,4R)-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)-3-(2-phenyl-4,6-dihydro-2H-furo[3,4- c]pyrazol-3-yl)urea MS (apci) m/z =448.2 (M + H). 82

1-((3S,4R)-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)-3-(2-phenyl-4,6-dihydro-2H- thieno[3,4-c]pyrazol-3-yl)urea MS (apci) m/z =464.2 (M + H). 83

1-((3S,4R)-4-(3,5-difluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3,4-dimethyl-1-phenyl-1H- pyrazol-5-yl)urea MS (apci) m/z = 470.2(M + H). 84

1-((3S,4R)-4-(3,5-difluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6- tetrahydrocyclopenta[c]pyrazol-3- yl)urea MS(apci) m/z = 482.2 (M + H). 85

1-((3S,4R)-4-(3,5-difluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-isopropyl-1-phenyl-1H- pyrazol-5-yl)urea MS (apci) m/z = 484.2(M + H). 86

1-((3S,4R)-4-(3,5-difluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-methyl-1-phenyl-1H- pyrazol-5-yl)urea MS (apci) m/z = 456.1(M + H). 87

1-((3S,4R)-4-(3,4-difluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6- tetrahydrocyclopenta[c]pyrazol-3- yl)urea MS(apci) m/z = 482.2 (M + H). 88

1-((3S,4R)-4-(3,5-difluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-4,6-dihydro-2H- furo[3,4-c]pyrazol-3-yl)urea MS (apci)m/z = 484.2 (M + H). 89

1-((3S,4R)-4-(3,5-difluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-4,6-dihydro-2H- thieno[3,4-c]pyrazol-3-yl)urea MS (apci)m/z = 500.2 (M + H). 90

1-((3S,4R)-4-(3,4-difluorophenyl)-1 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-4,6-dihydro-2H- furo[3,4-c]pyrazol-3-yl)urea MS (apci)m/z = 484.1 (M + H). 91

1-((3S,4R)-4-(3,4-difluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-4,6-dihydro-2H- thieno[3,4-c]pyrazol-3-yl)urea MS (apci)m/z = 500.1 (M + H). 92

1-((3S,4R)-4-(3,4-difluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3,4-dimethyl-1-phenyl-1H- pyrazol-5-yl)urea MS (apci) m/z = 470.2(M + H). 93

1-((3S,4R)-4-(3,4-difluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-3-phenyl-1H- pyrazol-5-yl)urea MS (apci) m/z = 456.1(M + H). 94

1-(3-(1-hydroxy-2-methylpropan- 2-yl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)urea MS (apci)m/z = 478.2 (M + H). 95

1-((3S,4R)-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)-3-(5-oxido-2-phenyl-4,6-dihydro-2H- thieno[3,4-c]pyrazol-3-yl)urea MS (apci)m/z = 480.1 (M + H). 96

1-((3S,4R)-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)-3-(1-methyl-3-(pyridin-4-yl)-1H- pyrazol-5-yl)urea MS (apci) m/z = 421.1 (M +H). 97

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (1-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-yl)urea MS (apci) m/z = 457.1 (M + H). 98

1-((3S,4R)-4-(3,5- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (1-methyl-3-phenyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 456.1 (M + H). 99

1-((3S,4R)-4-(3,5- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (1-methyl-3-(thiophen-2-yl)-1H-pyrazol-5-yl)urea MS (apci) m/z = 462.0 (M + H). 100

1-((3S,4R)-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)-3-(3-(methoxymethyl)-1-phenyl-1H- pyrazol-5-yl)urea MS (apci) m/z = 450.2(M + H). 101

1-((3S,4R)-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)-3-(3-(methoxymethyl)-4-methyl-1- phenyl-1H-pyrazol-5-yl)urea MS (apci) m/z =464.2 (M + H). 102

1-((3S,4R)-4- (3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (1-methyl-3-p-tolyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 470.1 (M + H). 103

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (1-methyl-3-m-tolyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 470.2 (M + H). 104

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (1-methyl-3-o-tolyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 470.4 (M + H). 105

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (3-(3-methoxyphenyl)-1-methyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 486.1 (M + H). 106

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (3-(2-methoxyphenyl)-1-methyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 486.2 (M + H). 107

1-(3-(4-fluorophenyl)-1-methyl- 1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)urea MS (apci) m/z = 438.2 (M +H). 108

1-((3S,4R)-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)-3-(3-(4-methoxyphenyl)-1-methyl-1H- pyrazol-5-yl)urea MS (apci) m/z = 450.2 (M +H). 109

1-((3S,4R)-1-(2-methoxyethyl)-4- (3- (trifluoromethyl)phenyl)pyrrolidin-3-yl)-3-(1-methyl-3-phenyl-1H- pyrazol-5-yl)urea MS (apci) m/z = 488.0(M + H). 110

1-((3S,4R)-4-(3-fluorophenyl)-1- (2-methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-3-phenyl-1H- pyrazol-5-yl)urea MS (apci) m/z = 438.2 (M +H). 111

1-((3S,4R)-4-(2,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (1-methyl-3-phenyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 455.9 (M + H). 112

1-((3S,4R)-4-(3-fluorophenyl)-1- (2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(4-fluorophenyl)-1-methyl- 1H-pyrazol-5-yl)urea MS (apci) m/z =456.1 (M + H). 113

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (3-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 474.1 (M + H). 114

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (3-(3-fluorophenyl)-1-methyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 474.1 (M + H). 115

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (3-(2-fluorophenyl)-1-methyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 474.1 (M + H). 116

1-((3S,4R)-4-(3-fluorophenyl)-1- (2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6- tetrahydrocyclopenta[c]pyrazol-3- yl)urea MS (apci)m/z = 464.2 (M + H). 117

1-(3-(1-hydroxy-2-methylpropan- 2-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2- methoxyethyl)-4-phenylpyrrolidin-3-yl)urea MS (apci) m/z = 492.3 (M + H). 118

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (3-(1-hydroxy-2-methylpropan-2-yl)-4-methyl-1-phenyl-1H- pyrazol-5-yl)urea MS (apci) m/z = 528.2 (M +H). 119

1-(3-(4-chlorophenyl)-1-methyl- 1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3- yl)urea MS (apci)m/z = 490.0 (M + H). 120

1-((3S,4R)-4-(2,5- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (3-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 474.1 (M + H). 121

methyl 4-(5-(3-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)ureido)-1-methyl-1H-pyrazol- 3-yl)benzoateMS (apci) m/z = 514.1 (M + H). 122

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (1-(2-hydroxyethyl)-3-phenyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 486.1 (M + H). 123

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (3-(methoxymethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 500.1 (M + H). 124

1-((3S,4R)-4-(3,5- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (3-(methoxymethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 500.1 (M + H). 125

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (1-methyl-3-(4-(methylthio)phenyl)-1H-pyrazol- 5-yl)urea MS (apci) m/z = 502.0 (M + H).126

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (1,3-diphenyl-1H-pyrazol-5- yl)urea MS(apci) m/z = 518.1 (M + H). 127

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (3-(3-methoxypropyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 528.1 (M + H). 128

1-((3S,4R)-4-(4-fluorophenyl)-1- (2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6- tetrahydrocyclopenta[c]pyrazol-3- yl)urea MS (apci)m/z = 464.1 (M + H). 129

1-(3,4-dimethyl-1-phenyl-1H- pyrazol-5-yl)-3-((3S,4R)-4-(4-fluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3- yl)urea MS (apci) m/z =452.1 (M + H). 130

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (3-(4-(2-methoxyethoxy)phenyl)-1-methyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 530.1 (M + H). 131

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (4-methoxy-3-methyl-1-phenyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 486.0 (M + H). 132

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (3-(hydroxymethyl)-4-methyl-1-phenyl-1H-pyrazol-3-yl)urea MS (apci) m/z = 486.1 (M + H). 133

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (3-(2-hydroxyethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 500.1 (M + H). 134

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (3-(2-methoxyethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 514.1 (M + H). 135

1-((3S,4R)-4-(3,4- difluorophenyl)1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H- pyrazol-5-yl)urea MS (apci) m/z = 500.1(M + H). 136

1-(3-(benzyloxy)-1-methyl-1H- pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3- yl)urea MS (apci) m/z =486.1 (M + H). 137

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (3-(2-methoxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 530.1 (M + H). 138

1-((3S,4R)-4-(3,5- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 500.1 (M + H). 139

trans-1-(3-ethoxy-4-methyl-1- phenyl-1H-pyrazol-5-yl)-3-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)urea MS (apci) m/z = 464.1 (M +H). 140

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (3-methoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 486.1 (M + H). 141

1-(3-(cyanomethoxy)-4-methyl-1- phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3- yl)ureaMS (apci) m/z = 511.1 (M + H).

The compounds of Table 8 were prepared according to the method ofExample 1 replacing the compound of Preparation B with the compound ofPreparation F or K and using the appropriate pyrazole intermediate.

TABLE 8 Ex. # Structure Name Data 142

1-((3S,4R)-4-(3,4-difluoro- phenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(4- methoxybenzyloxy)-4-methyl-1-phenyl-1H-pyrazol-5- yl)urea MS (apci) m/z = 592.1 (M + H). 143

1-((3S,4R)-4-(4- fluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-methoxy-4-methyl-1- phenyl-1H-pyrazol-5-yl)urea MS (apci) m/z =468.1 (M + H). 144

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-fluoroethoxy)-4- methyl-1-phenyl-1H-pyrazol- 5-yl)urea MS(apci) m/z = 518.1 (M + H). 145

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-hydroxy-2- methylpropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 544.3 (M + H).

The compounds of Table 9 were prepared according to the method ofExample 1 replacing the compound of Preparation B with the compound ofPreparation E, F, H or K and using the appropriate pyrazole intermediate

TABLE 9 Ex. # Structure Name Data 146

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (3-ethoxy-1-phenyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 486.2 (M + H). 147

1-(3-ethoxy-4-methyl-1-phenyl- 1H-pyrazol-5-yl)-3-((3S,4R)-4-(4-fluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3- yl)urea MS (apci) m/z= 482.3 (M + H). 148

1-(3-ethoxy-4-methyl-1-phenyl- 1H-pyrazol-5-yl)-3-((3S,4R)-4-(3-fluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3- yl)urea MS (apci) m/z= 482.3 (M + H). 149

1-((3S,4R)-4-(3,5- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (3-(2-hydroxyethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 516.3 (M + H). 150

1-(2-cyclohexyl-2,4,5,6- tetrahydrocyclopenta[c]pyrazol-3-yl)-3-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea MS (apci) m/z = 488.3 (M + H).

Example 151

1-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-(pyridin-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureaStep A: Preparation of2-(pyridin-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine

A solution of 2-oxocyclopentanecarbonitrile (0.4 g, 3.7 mmol, purchasedfrom AAT Pharmaceutical) and 4-hydrazinylpyridine hydrochloride (0.53 g,3.7 mmol) in methanol (35 mL) was sealed in a pressure vessel and heatedat 80° C. overnight. After removal of solvent in vacuo, the residue wastriturated with 1 N NaOH (20 mL) and extracted with DCM (3×25 mL). Thecombined organics was washed with brine, dried with MgSO₄, filtered andconcentrated to yield the crude product as brownish solid, which wasdirectly used in the next step. MS (apci) m/z=201.2 (M+H).

Step B: Preparation of1-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-(pyridin-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

To a mixture of2-(pyridin-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine (43 mg,0.21 mmol) in DCM (2 mL) at 0° C. was added DIEA (0.075 mL, 0.43 mmol)followed by triphosgene (25 mg, 0.086 mmol) in one portion. The reactionwas warmed up to ambient temperature and stirred for 2 hours. An aliquot(0.5 mL) of the reaction mixture (containing3-isocyanato-2-(pyridin-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole(12.1 mg, 0.0535 mmol)) was removed and treated with(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-aminebis(2,2,2-trifluoroacetate) (Preparation D, 20 mg, 0.0446 mmol) andN-ethyl-N-isopropylpropan-2-amine (38.8 μL, 0.223 mmol) sequentially.After stirring for 30 minutes, the reaction mixture was directlypurified by reverse-phase chromatography, eluting with 5-50%acetonitrile/water to yield the title final product as off-white solid(5 mg, 25% yield). MS (apci pos) m/z=447.2 (M+H).

The compounds of Table 10 were prepared according to the method ofExample 151 replacing the pyrazole input with the appropriate analog andreplacing the compound of Preparation D with the compound of PreparationF.

TABLE 10 Ex. # Structure Name Data 152

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-3-(5- methylpyrazin-2-yl)-1H- pyrazol-5-yl)urea MS (apci)m/z = 472.0 (M + H). 153

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(1,4-dimethyl-3-(5- methylpyrazin-2-yl)-1H- pyrazol-5-yl)urea MS(apci) m/z = 486.1 (M + H). 154

ethyl 5-(3-((3S,4R)-4-(3,4- difluoropheyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)ureido)-1-phenyl-1H-pyrazole-4-carboxylate MS (apci) m/z = 514.1 (M + H). 155

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-3-(pyrazin-2-yl)- 1H-pyrazol-5-yl)urea MS (apci) m/z = 458.1(M + H). 156

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-methoxy-1-methyl-4- phenyl-1H-pyrazol-5-yl)urea MS (apci) m/z =486.1 (M + H). 157

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-ethoxy-1-methyl-4-phenyl- 1H-pyrazol-5-yl)urea MS (apci) m/z =500.1 (M + H).

Example 158

1-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)ureadihydrochloride

tert-Butyl3-(3-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)ureido)-2-phenyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate(Example 79) was treated with 4N HCl in dioxane (2.0 mL, 0.017 mmol) andstirred at ambient temperature for 30 minutes. The resulting beigesuspension was filtered and the solids rinsed with Et₂O to afford theproduct as a tan solid (6.4 mg, 74% yield). MS (apci) m/z=447.1 (M+H).

Example 159

1-(5-acetyl-2-phenyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea

To a solution of1-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)urea dihydrochloride (Example158, 2.0 mg, 0.0039 mmol) and DIEA (0.0067 mL, 0.039 mmol) inacetonitrile (1.0 mL, 19 mmol) was added acetic acid (0.0011 mL, 0.019mmol) followed by HATU (2.9 mg, 0.0077 mmol). After stirring for 1 hourat ambient temperature, the reaction mixture was purified directly bysilica column chromatography, eluting with 0-10% MeOH/DCM to afford theproduct (0.7 mg, 37% yield). MS (apci) m/z=489.2 (M+H).

Example 160

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-(hydroxymethyl)-3-(methoxymethyl)-1-phenyl-1H-pyrazol-5-yl)urea

A solution of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-4,6-dihydro-2H-furo[3,4-c]pyrazol-3-yl)urea(Example 90, 250 mg, 0.517 mmol) in DCM (20 mL) was treated with 4NHCl/dioxane (5 mL). After concentrating to dryness, the residue wasconverted to the free base by partitioning with 1N NaOH and DCM, thenpurified by silica column chromatography, eluting with 2-4% MeOH/DCM toafford the product (29 mg, 11% yield). MS (apci) m/z=516.2 (M+H).

Example 161

4-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-methyl-1H-pyrazol-3-yl)benzoicacid

To a solution of methyl4-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-methyl-1H-pyrazol-3-yl)benzoate(Example 121, 79 mg, 0.15 mmol) in THF (4.0 mL, 0.15 mmol) and MeOH (2.0mL, 49 mmol) at 0° C. was added LiOH (2M aqueous) (0.15 mL, 0.31 mmol).This reaction was stirred at ambient temperature and additional LiOH wasadded until complete conversion was observed by HPLC analysis(approximately 2 days). After acidification with 2M HCl (1 mL), themixture was diluted with water (10 mL), extracted with DCM (20 mL), thenextracted with 10% MeOH/DCM (3×10 mL). The combined organic phases werewashed with brine (25 mL), dried with MgSO₄, filtered and concentratedto give the product as a white solid (70 mg, 91% yield). MS (apci)m/z=500.1 (M+H).

Example 162

4-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-methyl-1H-pyrazol-3-yl)benzamide

To a solution of4-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-methyl-1H-pyrazol-3-yl)benzoicacid (Example 161, 12 mg, 0.024 mmol) in DMF (0.5 mL, 0.024 mmol) wasadded N-methylmorpholine (0.0079 mL, 0.072 mmol), NH₃ (0.5M in dioxane)(0.096 mL, 0.048 mmol) and HATU (10 mg, 0.026 mmol) sequentially. Thereaction mixture was stirred overnight at ambient temperature andpurified by reverse-phase column chromatography, eluting with 5-50%acetonitrile/water, to afford the title compound (5.1 mg, 43% yield). MS(apci) m/z=499.1 (M+H).

Example 163

4-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-methyl-1H-pyrazol-3-yl)-N-methylbenzamide

Prepared according to the method described in Example 162, substitutingNH₃ with methylamine (2 M in THF). MS (apci) m/z=513.1 (M+H).

Example 164

4-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-methyl-1H-pyrazol-3-yl)-N,N-dimethylbenzamide

Prepared according to the method described in Example 162, substitutingNH₃ with dimethylamine (2 M in THF). MS (apci) m/z=5527.1 (M+H).

Example 165

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(4-(hydroxymethyl)phenyl)-1-methyl-1H-pyrazol-5-yl)urea

To a suspension of methyl4-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-methyl-1H-pyrazol-3-yl)benzoate(Example 121; 20 mg, 0.039 mmol) in THF (2 mL, 0.081 mmol) at 0° C.under N₂ was added lithium aluminum hydride (1M bis-THF solution intoluene) (0.078 mL, 0.078 mmol). The reaction mixture was stirred at 0°C. for 1 hour, then quenched by the addition of 3 μL H₂O and 3 μL 1Maqueous NaOH, followed by 9 L H₂O. The mixture was stirred at ambienttemperature for 4 hours, then filtered through a syringe filter, rinsedwith THF (2 mL), and concentrated to a white solid. The solid waspurified by reverse phase chromatography eluting with 5-50%acetonitrile/water, to afford the title compound (10 mg, 53% yield). MS(apci) m/z=486.1 (M+H).

Example 166

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-3-(4-(methylsulfonyl)phenyl)-1H-pyrazol-5-yl)ureaStep A: Preparation of phenyl1-methyl-3-(4-(methylthio)phenyl)-1H-pyrazol-5-ylcarbamate

Prepared according to Step A of Example 1, replacing the3-tert-butyl-1-phenyl-1H-pyrazol-5-amine with1-methyl-3-(4-(methylthio)phenyl)-1H-pyrazol-5-amine (Intermediate P121)to afford the product. MS (apci) m/z=340.0 (M+H).

Step B: Preparation of phenyl1-methyl-3-(4-(methylsulfonyl)phenyl)-1H-pyrazol-5-ylcarbamate

To a solution of phenyl1-methyl-3-(4-(methylthio)phenyl)-1H-pyrazol-5-ylcarbamate (110 mg,0.324 mmol) in DCM (5 mL, 0.295 mmol) at 0° C. was added MCPBA (70-75%in H₂O) (72.6 mg, 0.295 mmol) in one portion. The reaction mixture wasallowed to warm to ambient temperature and stirred for 2 hours, and thenanother portion of MCPBA (72.6 mg, 0.295 mmol) was added. After stirringfor 5 hours at ambient temperature, the mixture was diluted with DCM (25mL) and washed with saturated aqueous NaHCO₃ (2×10 mL) and saturatedaqueous Na₂S₂O₃ (3×10 mL). The organic layer was dried with MgSO₄,filtered and concentrated in vacuo to give the crude product (101 mg,92.3% yield). MS (apci) m/z=372.0 (M+H).

Step C: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-3-(4-(methylsulfonyl)phenyl)-1H-pyrazol-5-yl)urea

Prepared according to Step B of Example 1, substituting phenyl1-methyl-3-(4-(methylsulfonyl)phenyl)-1H-pyrazol-5-ylcarbamate forphenyl 3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate and substitutingthe compound of Preparation F for the compound of Preparation B. MS(apci) m/z=534.1 (M+H).

Example 167

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-fluoro-3-methyl-1-phenyl-1H-pyrazol-5-yl)ureaStep A: Preparation of phenyl 3-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate

Prepared according to the method of Example 1, Step A, replacing3-tert-butyl-1-phenyl-1H-pyrazol-5-amine with3-methyl-1-phenyl-1H-pyrazol-5-amine to afford the product. MS (apci)m/z=294.1 (M+H).

Step B: Preparation of phenyl4-fluoro-3-methyl-1-phenyl-H-pyrazol-5-ylcarbamate

To a solution of phenyl 3-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (20mg, 0.0682 mmol) in acetonitrile (0.5 mL) was added Selectfluor (26.6mg, 0.0750 mmol) in small portions at ambient temperature and thereaction mixture was stirred overnight. The reaction mixture waspurified directly by reverse-phase column chromatography, eluting with5-65% acetonitrile/water, to afford the product as a white foamy solid(12.4 mg, 58.4% yield). MS (apci) m/z=312.0 (M+H).

Step C: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-fluoro-3-methyl-1-phenyl-H-pyrazol-5-yl)urea

Prepared according to the method of Example 1, Step B, substitutingphenyl 4-fluoro-3-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate for phenyl3-tert-butyl-1-phenyl-H-pyrazol-5-ylcarbamate and substituting thecompound of Preparation F for the compound of Preparation B. MS (apci)m/z=474.1 (M+H).

Example 168

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-fluoro-1-methyl-3-phenyl-1H-pyrazol-5-yl)urea

Prepared using the same procedure as Example 167, substituting1-methyl-3-phenyl-1H-pyrazol-5-amine for3-methyl-1-phenyl-1H-pyrazol-5-amine. MS (apci) m/z=474.1 (M+H).

Example 169

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-fluoro-1,3-diphenyl-1H-pyrazol-5-yl)urea

Prepared using the same procedure as Example 167, substituting1,3-di-phenyl-1H-pyrazol-5-amine for3-methyl-1-phenyl-1H-pyrazol-5-amine. MS (apci) m/z=536.1 (M+H).

Example 170

2-methoxyethyl4-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-methyl-1H-pyrazol-3-yl)benzoateStep A: Preparation of Lithium4-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-methyl-1H-pyrazol-3-yl)benzoate

To a solution of methyl4-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-methyl-1H-pyrazol-3-yl)benzoate(Example 121; 158 mg, 0.308 mmol) in THF (4 mL, 0.308 mmol) and MeOH(2.00 mL, 49.4 mmol) at 0° C. was added LiOH (2M aqueous) (0.308 mL,0.615 mmol). The reaction mixture was warmed to ambient temperature andstirred for 48 hours. Another portion of LiOH was added (70 μL, 0.4equiv.) and the reaction mixture was stirred for an additional 4 days.The reaction mixture was concentrated to dryness and used directly inthe next step, assuming quantitative yield. MS (apci) m/z=500.1 (M+H).

Step B: Preparation of 2-methoxyethyl4-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-methyl-1H-pyrazol-3-yl)benzoate

To a solution of lithium4-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-methyl-1H-pyrazol-3-yl)benzoate(15 mg, 0.030 mmol) in DMF (0.5 mL, 0.030 mmol) was added DIEA (0.016mL, 0.089 mmol) and 2-methoxyethanol (9.0 mg, 0.12 mmol), followed byHATU (17 mg, 0.045 mmol). The reaction mixture was stirred overnight atambient temperature, then purified directly by reverse-phase columnchromatography, eluting with 5-65% acetonitrile/water, to afford theproduct as a white foamy solid (1.8 mg, 11% yield). MS (apci) m/z=558.0(M+H).

Example 171

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(5,5-dioxido-2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)ureaStep A: Preparation of2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-amine

A suspension of 4-oxotetrahydrothiophene-3-carbonitrile (1.00 g, 7.86mmol) and phenylhydrazine hydrochloride (1.25 g, 8.65 mmol) in absoluteEtOH (40 mL, 7.86 mmol) was refluxed for 2 hours. The mixture wasconcentrated and the residue was triturated with 1N aqueous NaOH (40mL). The solid was collected by filtration, washed sequentially with 0.1N aqueous NaOH, water, and hexanes, then dried in vacuo to yield theproduct (1.62 g, 95% yield) as a white solid. MS (apci) m/z=218.1.

Step B: Preparation of phenyl2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-ylcarbamate

To a suspension of 2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-amine(500 mg, 2.30 mmol) in EtOAc (10.0 mL, 2.30 mmol) was added NaOH (2.30mL, 2M aqueous, 4.60 mmol) followed by phenylchloroformate (0.40 mL,3.22 mmol) dropwise at ambient temperature. After stirring for 2 hours,additional phenylchloroformate (0.14 mL) was added. Stirring wascontinued for 5 minutes, and then another portion of phenylchloroformate (0.081 mL) was added and the mixture was stirred for afurther 16 hours. The reaction mixture was diluted with EtOAc and thephases were separated. The organic phase was washed with water and brine(25 mL each), dried over Na₂SO₄, filtered and concentrated. The residuewas purified by reverse-phase column chromatography, eluting with 5-70%acetonitrile/water to afford the product (0.50 g, 64% yield) as a whitesolid (83% purity). MS (apci) m/z=338.1.

Step C: Preparation of phenyl(5,5-dioxido-2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)carbamate

To a milky solution of phenyl2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-ylcarbamate (100 mg, 0.29mmol) in DCM (5 mL) at 0° C. was added MCPBA (170 mg, 70-75% watercomplex, 0.74 mmol). The mixture was removed from the bath and stirredat ambient temperature for 10 minutes, then diluted with DCM (20 mL) andwashed successively with saturated NaHCO₃ (3×10 mL), saturated Na₂S₂O₃(2×10 mL) and brine (10 mL). The organic layer was dried over Na₂SO₄ andconcentrated to afford the product (107 mg, 98% yield) as a pale orangefoam which was used without purification. MS (apci) m/z=371.4.

Step D: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(5,5-dioxido-2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)urea

To a solution of(3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminetrifluoroacetate (Preparation E; 60 mg, 0.12 mmol) and phenyl(5,5-dioxido-2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)carbamate(50.3 mg, 0.14 mmol) in anhydrous DMA (2 mL) was added DIEA (97 μL, 0.56mmol). The mixture was stirred at ambient temperature for 15 hours. Thereaction mixture was then partitioned between saturated NH₄Cl (20 mL)and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (2×10 mL)and the combined organic phases were washed with water (5×10 mL) andbrine (10 mL) then dried over Na₂SO₄ and concentrated. Purification ofthe crude product by silica column chromatography eluting with 2%MeOH/DCM afforded the product as a pale yellow foam (33 mg, 50% yield).MS (apci) m/z=532.1.

Example 172

1-(5,5-dioxido-2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea

Prepared according to the procedure used for Example 171, replacing(3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminetrifluoroacetate (Preparation E) with(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride(Preparation D) in Step D. MS (apci) m/z=496.0 (M+H).

Example 173

1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidi-3-yl)-3-(5,5-dioxido-2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)urea

Prepared using the same procedure as Example 171, substituting(3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminetrifluoroacetate (Preparation E) for(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation F). MS (apci) m/z=532.0 (M+H).

Example 174

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-(methylsulfonyl)ethoxy)-1-phenyl-1H-pyrazol-5-yl)urea Step A: Preparation ofphenyl4-methyl-3-(2-(methylthio)ethoxy)-1-phenyl-1H-pyrazol-5-ylcarbamate

Prepared according to the method described for Example 171, Step B,replacing 2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-amine with4-methyl-3-(2-(methylthio)ethoxy)-1-phenyl-1H-pyrazol-5-amine(Intermediate P206). MS (apci) m/z=384.0 (M+H).

Step B: Preparation of phenyl4-methyl-3-(2-(methylsulfonyl)ethoxy)-1-phenyl-1H-pyrazol-5-ylcarbamate

Phenyl4-methyl-3-(2-(methylthio)ethoxy)-1-phenyl-1H-pyrazol-5-ylcarbamate(0.217 g, 0.566 mmol) was treated with THF (10 mL) and cooled to 0° C. Asolution of 3-chlorobenzoperoxoic acid (MCPBA) with THF (4 mL) was addedto the reaction mixture. After stirring for 1 hour, the mixture waswarmed to ambient temperature and stirred for 2 hours. The reactionmixture was treated with EtOAc, quenched with Na₂S₂O₃ and water,extracted with EtOAc, washed with NaHCO₃ and brine, dried over MgSO₄,filtered and concentrated in vacuo. The resultant crude product waspurified by silica column chromatography to afford the product (0.207 g,88.0% yield). MS (apci) m/z=416.0 (M+H).

Step C: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-meth-3-(2-(methyl-3-(2-(methylsulfonyl)ethoxy)-1-phenyl-1H-pyrazol-5-yl)urea

To (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation F; 50 mg, 0.15 mmol) in DCM (5 mL) at 0° C. was addedphenyl4-methyl-3-(2-(methylsulfonyl)ethoxy)-1-phenyl-1H-pyrazol-5-ylcarbamate(63 mg, 0.15 mmol) followed by addition of TEA (0.064 mL, 0.46 mmol).The resulting mixture was allowed to warm to ambient temperature andstirred for 17 hours. The reaction mixture was then treated with EtOAc,washed with saturated NH₄Cl, saturated NaHCO₃, and brine, dried withMgSO₄, filtered, concentrated, and purified by silica columnchromatography, eluting with 3% MeOH/DCM to yield the title product as awhite solid (47 mg, 53% yield). MS (apci) m/z=578.0 (M+H).

Example 175

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-(hydroxymethyl)-1-phenyl-1H-pyrazol-5-yl)urea

To a solution of ethyl5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazole-4-carboxylate(Example 154; 55 mg, 0.11 mmol) in THF (2 mL) at 0° C. under N₂ wasadded dropwise lithium aluminum hydride (1M bis-THF solution in toluene,0.21 mL, 0.21 mmol). The reaction was stirred at 0° C. for 1.5 hours,then at ambient temperature for 3 hours. The reaction was quenched bysequential addition of H₂O (0.008 mL), 1M aqueous NaOH (0.008 mL), andH₂O (0.024 mL). After stirring at ambient temperature for 2 hours, thereaction mixture was filtered, rinsed with THF (2 mL), and concentratedin vacuo. The crude product was purified by preparative TLC (0.5 mmplate) eluting with 10% MeOH/DCM to yield the product as a white solid(6 mg, 11% yield). MS (apci) m/z=472.0 (M+H).

Example 176

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((R)-2,3-dihydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

To a solution of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea(Example 76; 65.0 mg, 0.111 mmol) in THF (2 mL) was added aqueous 1M HCl(2 mL). The reaction mixture was stirred at ambient temperature for 75minutes and then concentrated to remove THF. The remaining aqueoussolution was diluted with H₂O (2 mL) and treated with 2M NaOH to pH=10.The resulting milky mixture was treated with NaCl to saturation andextracted with EtOAc (2×). The combined organic extracts were dried overMgSO₄ and filtered through packed Celite®. The eluent was concentratedto a colorless gel that was washed with Et₂O and dried in vacuum toprovide the title compound as a white solid (53 mg, 88% yield). MS(apci) m/z=546.1 (M+H).

Example 177

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((S)-2,3-dihydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared from 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea(Example 77; 50.0 mg, 0.0854 mmol) according to the procedure describedfor Example 176, to provide title compound as a white solid (38 mg, 82%yield). MS (apci) m/z=546.2 (M+H).

Example 178

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-hydroxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureahydrochloride

To1-(3-(2-(tert-butyldimethylsilyloxy)ethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea(Preparation U-1; 46 mg, 0.073 mmol) in DCM (2 mL) at ambienttemperature was added 2N HCl (22 mL, 0.44 mmol). After stirring for 1hour, the reaction mixture was concentrated in vacuo and rinsed withEt₂O to give the product as the HCl salt (45 mg, 100% yield). MS (apci)m/z=516.1 (M+H).

Example 179

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((S)-2-hydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureahydrochloride

To1-(3-((S)-2-(tert-butyldimethylsilyloxy)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea(Preparation U-2; 33 mg, 0.051 mmol) in DCM (2 mL) at ambienttemperature was added 2N HCl (0.15 mL, 0.31 mmol). After stirring for 1hour, the reaction mixture was concentrated in vacuo and rinsed withEt₂O to give the product HCl salt (29 mg, 100% yield). MS (apci)m/z=530.3 (M+H).

Example 180

1-((3R,4S)-4-hydroxy-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea Step A: Preparation of(3R,4R)-tert-butyl 3-azido-4-hydroxypyrrolidine-1-carboxylate

tert-Butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (15.42 g, 83.25mmol),(1S,2S)-(−)-[1,2-cyclohexanediamino-N,N-bis(3,5-di-t-butylsalicylidene)]chromium (III) chloride (1.181 g, 1.665 mmol) and azidotrimethylsilane(12.79 mL, 91.58 mmol) were stirred at ambient temperature under anitrogen atmosphere for 18 hours. The resultant dark red-brown mixturewas treated with MeOH (100 mL) and K₂CO₃ (13.81 g, 99.90 mmol) and thereaction was stirred at ambient temperature for 5 hours. The solutionwas filtered through a pad of Celite®, concentrated and taken up inEtOAc (100 mL) and water (50 mL). The layers were separated and theaqueous layer was extracted with EtOAc. The combined organic extractswere washed with saturated aqueous NaHCO₃, water, and brine, dried withMgSO₄ and concentrated to provide a brown oil. The oil was purified bysilica column chromatography eluting with 20% EtOAc/hexanes to providethe title compound (ee=93%, 3.99 g, 102% yield). MS (apci) m/z=129.0(M+H-Boc).

Step B: Preparation of (3R,4R)-4-azidopyrrolidin-3-ol hydrochloride

(3R,4R)-tert-butyl 3-azido-4-hydroxypyrrolidine-1-carboxylate (9.0 g, 39mmol) and 4N HCl in dioxane (15 mL, 59 mmol) were combined in DCM (30mL) and stirred at ambient temperature for 18 hours. The reaction wasconcentrated in vacuo to provide the title compound (6.5 g, 100% yield)as a yellow oil. MS (apci) m/z=129.0 (M+H).

Step C: Preparation of (3R,4R)-4-azido-1-(2-methoxyethyl)pyrrolidin-3-ol

(3R,4R)-4-azidopyrrolidin-3-ol hydrochloride (6.5 g, 39.5 mmol),1-bromo-2-methoxyethane (6.59 g, 47.4 mmol) and DIEA (13.8 mL, 79.0mmol) were combined in 10 mL of DMF and stirred at ambient temperaturefor 18 hours. MP-TsOH (39.5 g, 158 mmol) was added and the reaction wasshaken for 1 hour, filtered, and the resin was washed with DCM. Theamine was released from the resin by shaking with 7N NH₃ in MeOH (113mL, 790 mmol) and DCM (113 mL) for 1 hour. The reaction was filtered andthe resin was washed with DCM. The combined filtrates were concentratedto provide the crude title compound (7.09 g, 96.4% yield). MS (apci)m/z=187.0 (M+H).

Step D: Preparation of (3R,4R)-4-amino-1-(2-methoxyethyl)pyrrolidin-3-ol

(3R,4R)-4-azido-1-(2-methoxyethyl)pyrrolidin-3-ol (3.0 g, 16.1 mmol) and10% Pd/C (1.71 g, 1.61 mmol) were combined in 40 mL of MeOH and thereaction was shaken at 40 psi H₂ in a Parr shaker for three days. Thereaction was filtered through Celite® and concentrated to afford thetitle compound (2.53 g, 98.0% yield) as a brown oil. MS (apci) m/z=161.1(M+H).

Step E: Preparation of tert-butyl (3R,4R)-4-hydroxy-1-(2-methoxyethyl)pyrrolidin-3-ylcarbamate

(3R,4R)-4-Amino-1-(2-methoxyethyl)pyrrolidin-3-ol (2.50 g, 15.6 mmol),Boc₂O (4.09 g, 18.7 mmol) and PS-DMAP (0.191 g, 1.56 mmol) were combinedin 50 mL of DCM and shaken at ambient temperature for 18 hours. Thereaction was filtered, concentrated and purified by silica columnchromatography, eluting with 5-20% EtOAc/hexanes, to afford the titlecompound (3.17 g, 78.0% yield). MS (apci) m/z=261.0 (M+H).

Step F: Preparation of (R)-tert-butyl1-(2-methoxyethyl)-4-oxopyrrolidin-3-ylcarbamate

A solution of oxalyl chloride (33.51 μL, 0.3841 mmol) in 5 mL of DCM wascooled to −78° C. and DMSO (54.52 μL, 0.7683 mmol) was added dropwise.The reaction was stirred for 15 minutes and a solution of tert-butyl(3R,4R)-4-hydroxy-1-(2-methoxyethyl)pyrrolidin-3-ylcarbamate (50 mg,0.1921 mmol) in 2 mL of DCM was added dropwise. The reaction was allowedto warm to −40° C. over 1 hour and then cooled to −78° C. Triethylamine(267.7 μL, 1.921 mmol) was added dropwise, and the reaction was allowedto warm to 0° C. over 1 hour, then quenched with water and extractedwith ether (40 mL). The organic layer was dried over MgSO₄, filtered andconcentrated to afford the crude title compound (32 mg, 65% yield). MS(apci) m/z=259.0 (M+H).

Step G: Preparation of tert-butyl(3R,4S)-4-hydroxy-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-ylcarbamate

(R)-tert-butyl 1-(2-methoxyethyl)-4-oxopyrrolidin-3-ylcarbamate (17.0mg, 0.0658 mmol) was dissolved in THF (2 mL) and the solution was cooledto −78° C. A solution of phenyllithium in dibutyl ether (395 μL, 0.197mmol) was added dropwise and the reaction was stirred at −78° C. for 1hour and then allowed to warm to ambient temperature over 1 hour. Thereaction was poured into brine (10 mL) and extracted with severalportions of ether. The combined organic extracts were dried,concentrated and purified by reverse-phase column chromatography,eluting with 0-50% acetonitrile/water to provide the title compound asabout a 4:1 mixture with tert-butyl(3R,4R)-4-hydroxy-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-ylcarbamate(8.5 mg, 38% yield). MS (apci) m/z=337.1 (M+H).

Step H: Preparation of(3S,4R)-4-amino-1-(2-methoxyethyl)-3-phenylpyrrolidin-3-oldihydrochloride

To a solution of the product from Step G (7.0 mg, 0.0208 mmol) in 0.1 mLof isopropanol was added a solution of HCl in isopropanol (29.7 μL,0.208 mmol). The reaction mixture was stirred at ambient temperature for1 hour, then concentrated to afford the title compound as about a 4:1mixture with (3R,4R)-4-amino-1-(2-methoxyethyl)-3-phenylpyrrolidin-3-oldihydrochloride (6.5 mg, 101% yield). MS (apci) m/z=237.1 (M+H).

Step I: Preparation of1-((3R,4S)-4-hydroxy-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

The product from Step H (6.5 mg, 0.021 mmol) and DIEA (11 μL, 0.063mmol) were combined in 0.5 mL of DCM and cooled to 0° C. Phenyl2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (7.4 mg,0.023 mmol) was added and the reaction was allowed to warm to ambienttemperature over 1 hour. The reaction was concentrated and purified byreverse-phase column chromatography, eluting with 0-60%acetonitrile/water to afford the title compound (3.8 mg, 39% yield). MS(apci) m/z=462.2 (M+H).

Example 181

1-((3R,4S)-4-fluoro-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

An approximately 2:1 mixture of1-((3R,4S)-4-hydroxy-1-(2-methoxyethyl)-4-phenyl-pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureaand1-((3R,4R)-4-hydroxy-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea (5.0 mg, 0.011 mmol)(obtained as described in Example 177, Step I) was dissolved in DCM (2mL) and cooled to −78° C. DAST (1.7 mg, 0.011 mmol) was added and thereaction was slowly allowed to warm to ambient temperature overnight.The reaction was quenched with MeOH, concentrated and purified byreverse phase MPLC to afford the title compound as about a 1:3 mixturewith1-((3R,4R)-4-fluoro-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea(2.6 mg, 40% yield). The isomers were not separated. MS (apci) m/z=464.1(M+H).

Example 182

1-(trans-4-phenyl-1-(2-(trifluoromethoxy)ethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea Step A: Preparation oftrans-tert-butyl3-phenyl-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureido)pyrrolidine-1-carboxylate

To a solution of trans-tert-butyl3-amino-4-phenylpyrrolidine-1-carboxylate (Preparation A2; 40 mg, 0.15mmol) in DMA (0.5 mL, 0.15 mmol) was added phenyl2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (Example38, Step C; 58 mg, 0.18 mmol) followed by cooling in an ice bath. DIEA(0.080 mL, 0.46 mmol) was added to the reaction mixture, which was thenallowed to warm to ambient temperature overnight. The reaction mixturewas directly purified by reverse-phase column chromatography, elutingwith 5-75% acetonitrile/water, to afford the product as a white solid(30 mg, 41% yield). MS (apci) m/z=488.0 (M+H).

Step B: Preparation of1-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-(trans-4-phenylpyrrolidin-3-yl)ureahydrochloride salt

trans-tert-Butyl3-phenyl-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureido)pyrrolidine-1-carboxylate(30 mg, 0.062 mmol) was treated with 4N HCl in dioxane and stirred atambient temperature for 15 hours, then concentrated in vacuo andtriturated in Et₂O to afford the product (20 mg, 83% yield). MS (apci)m/z=388.1 (M+H).

Step C: Preparation of1-(trans-4-phenyl-1-(2-(trifluoromethoxy)ethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

To a DMF (0.5 mL) solution of 1-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-(trans-4-phenylpyrrolidin-3-yl)ureahydrochloride salt (16 mg, 0.038 mmol) was addedN-ethyl-N-isopropylpropan-2-amine (21 μL, 0.11 mmol) and1-bromo-2-(trifluoromethoxy)ethane (8.7 mg, 0.045 mmol) and stirred atambient temperature for 3 hours, then heated to 40° C. for 15 hours. Thereaction mixture was directly purified by purified by reverse-phasecolumn chromatography, eluting with 5-75% acetonitrile/water, to affordthe title compound (10 mg, 50% yield). MS (apci) m/z=499.9 (M+H).

Example 183

1-(trans-1-(2-(methylthio)ethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

Prepared as in Example 182, substituting1-bromo-2-(trifluoromethoxy)ethane with (2-chloroethyl)(methyl)sulfaneto afford the product (2.6 mg, 24% yield) as a beige solid. MS (apci)m/z=462.1 (M+H).

Example 184

1-((3S,4R)-1-((S)-2-methoxypropyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea Step A: (S)-2-methoxypropylmethanesulfonate

A solution of (S)-2-methoxypropan-1-ol (451 mg, 5.00 mmol) and DIEA(1.74 mL, 10.0 mmol) in dry CH₂Cl₂ (4 mL) was cooled to 0° C. and MsCl(0.406 mL, 5.25 mmol) was added over 2 minutes. The mixture was stirredfor 3 hours during which time the mixture reached ambient temperature.The mixture was washed with chilled H₂O, saturated NaHCO₃ and dried overNa₂SO₄. The dried solution was filtered through packed Celite® andconcentrated to give the title product as a light gold oil (821 mg, 98%yield). ¹H NMR (CDCl₃) δ 4.22 (m, 1H), 4.13 (m, 1H), 3.63 (m, 1H), 3.40(s, 3H), 3.06 (s, 3H), 1.20 (d, J=6.4 Hz, 3H).

Step B: Tert-butyl(3S,4R)-1-((S)-2-methoxypropyl)-4-phenylpyrrolidin-3-ylcarbamate

To a solution of tert-butyl (3S,4R)-4-phenylpyrrolidin-3-ylcarbamate(Commercially available, 262 mg, 1.00 mmol) and DIEA (348 μL, 2.00 mmol)in DMF (2.0 mL) was added (S)-2-methoxypropyl methanesulfonate (252 mg,1.50 mmol). The reaction was heated at 60° C. for 21 hours andadditional (S)-2-methoxypropyl methanesulfonate (84.0 mg) was added. Thereaction mixture was heated 60° C. for 2 hours, cooled to ambienttemperature and added to H₂O (8 mL). The mixture was extracted withEtOAc (3×) and the combined extracts were washed with saturated NaCl(2×) and dried with MgSO₄. The dried solution was filtered through aSiO₂ plug eluting with EtOAc. The solution was concentrated to give thecrude title compound as a light gold syrup (462 mg, 138% yield) that wasused directly in the next step. MS (apci) m/z=335.1 (M+H).

Step C: (3S,4R)-1-((S)-2-methoxypropyl)-4-phenylpyrrolidin-3-aminedihydrochloride

To a solution of the crude tert-butyl(3S,4R)-1-((S)-2-methoxypropyl)-4-phenylpyrrolidin-3-ylcarbamate inEtOAc (10 mL) was added 4 M HCl in dioxane (10.0 mL, 40.0 mmol). Thereaction mixture was stirred at ambient temperature for 3 hours and thendiluted with MTBE (50 mL). The resulting precipitate was collected,washed with MTBE and dried in vacuum to afford the title compound as atacky white solid (276 mg, 90% yield). MS (apci) m/z=235.1 (M+H).

Step D:1-((3S,4R)-1-((S)-2-methoxypropyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

To a solution of(3S,4R)-1-((S)-2-methoxypropyl)-4-phenylpyrrolidin-3-aminedihydrochloride (56.2 mg, 0.240 mmol) in dry DMF (0.8 mL) was added DIEA(139 μL, 0.796 mmol) and the mixture stirred at ambient temperature for5 minutes. Phenyl2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (Example38, Step E; 75.1 mg, 0.200 mmol) was added and the mixture stirred atambient temperature for 4 hours. The mixture was added to H₂O (5 mL) andwas extracted with EtOAc (3×). The combined extracts were washed with 1MNaOH (2×), H₂O and saturated NaCl. The solution was dried with MgSO₄,filtered and concentrated in vacuo. The residue was purified by silicachromatography eluting with EtOAc to provide the title compound as awaxy, white solid (31 mg, 34% yield). MS (apci) m/z=460.1 (M+H).

Example 185

1-((3,4-trans)-4-phenyl-1-(4,4,4-trifluorobutyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

Prepared as in Example 182, substituting1-bromo-2-(trifluoromethoxy)ethane with 4-bromo-1,1,1-trifluorobutane toafford the product (10 mg, 57% yield) as a white solid. MS (apci)m/z=498.2 (M+H).

Example 186

1-((3S,4R)-1-(cyanomethyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureaStep A: Preparation of tert-butyl(3S,4R)-1-(cyanomethyl)-4-(3,4-difluorophenyl) pyrrolidin-3-ylcarbamate

To a solution of tert-butyl(3S,4R)-4-(3,4-difluorophenyl)pyrrolidin-3-ylcarbamate (100.0 mg, 0.3352mmol, purchased from ACS Scientific) and TEA (51.39 μL, 0.3687 mmol) inTHF (1.5 mL) was added 2-bromoacetonitrile (25.68 μL, 0.3687 mmol)dropwise. After stirring for two hours at ambient temperature, thereaction mixture was filtered and concentrated. The crude material waspurified by silica column chromatography, eluting with 33% EtOAc/Hexanesto yield the product as white solid (98 mg, 87% yield). MS (apci pos)m/z=338.0 (M+H).

Step B: Preparation of2-((3S,4R)-3-amino-4-(3,4-difluorophenyl)pyrrolidin-1-yl) acetonitrilehydrochloride

A mixture of tert-butyl(3S,4R)-1-(cyanomethyl)-4-(3,4-difluorophenyl)pyrrolidin-3-ylcarbamate(20 mg, 0.059 mmol) in HCl (150 μL, 0.59 mmol, 4 N dioxane) was stirredat ambient temperature for 15 minutes, then concentrated in vacuo,triturated with ether and dried on high vacuum to yield the product aswhite solid (16 mg, 99% yield). MS (apci pos) m/z=238.0 (M+H).

Step C: Preparation of 1-((3S,4R)-1-(cyanomethyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

To a clear solution of2-((3S,4R)-3-amino-4-(3,4-difluorophenyl)pyrrolidin-1-yl)acetonitrilehydrochloride (16 mg, 0.058 mmol) and phenyl2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (19 mg,0.058 mmol) in DMA (0.5 mL) was added DIEA (0.041 mL, 0.23 mmol)dropwise at ambient temperature. After stirring for 1 hour, the reactionmixture was directly purified by reverse-phase column chromatography,eluting with 5-55% acetonitrile/water to yield the product as whitesolid (18 mg, 65% yield). MS (apci pos) m/z=463.0 (M+H).

Example 187

1-((3S,4R)-1-(cyanomethyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(3-(2-methoxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

To a clear solution of2-((3S,4R)-3-amino-4-(3,4-difluorophenyl)pyrrolidin-1-yl)acetonitrilehydrochloride (Example 186, Step B, 10 mg, 0.037 mmol) and phenyl3-(2-methoxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (13 mg,0.037 mmol) in DMA (180 μL, 0.037 mmol) was added DIEA (32 μL, 0.18mmol) dropwise at ambient temperature. The reaction was heated to about60° C. briefly (about 1 minute) then cooled to ambient temperature andstirred for 20 minutes. The reaction mixture was directly purified byreverse-phase column chromatography, eluting with 5-65%acetonitrile/water to yield the product as white solid (12 mg, 64%yield). MS (apci pos) m/z=511.1 (M+H).

Example 188

1-((3,4-trans)-1-(cyanomethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea Step A: Preparation oftert-butyl (3,4-trans)-1-(cyanomethyl)-4-phenylpyrrolidin-3-ylcarbamate

To a solution of tert-butyl (3,4-trans)-4-phenylpyrrolidin-3-ylcarbamate(206.0 mg, 0.7852 mmol, Preparation A) and TEA (120.4 μL, 0.8637 mmol)in THF (3 mL) was added 2-bromoacetonitrile (60.16 μL, 0.8637 mmol)dropwise. After stirring at ambient temperature overnight, the reactionmixture was filtered and concentrated to yield the product as whitesolid (230 mg, 97% yield). MS (apci pos) m/z=302.1 (M+H).

Step B: Preparation of2-((3,4-trans)-3-amino-4-phenylpyrrolidin-1-yl)acetonitrilehydrochloride

A mixture of tert-butyl(3,4-trans)-1-(cyanomethyl)-4-phenylpyrrolidin-3-ylcarbamate (230 mg,0.763 mmol) and HCl (4770 μL, 19.1 mmol, 4 N dioxane) was stirred atambient temperature for 2 hours, then concentrated in vacuo, treatedwith ether and dried on high vacuum to yield the product as apale-yellowish solid (180 mg, 99% yield). MS (apci pos) m/z=202.1 (M+H).

Step C: Preparation of1-((3,4-trans)-1-(cyanomethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

To a clear solution of2-(3,4-trans)-3-amino-4-phenylpyrrolidin-1-yl)acetonitrile hydrochloride(33 mg, 0.14 mmol) and phenyl2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (40 mg,0.13 mmol) in DMA (630 L) was added DIEA (110 μL, 0.63 mmol) dropwise atambient temperature. After stirring at ambient temperature overnight,the reaction mixture was directly purified by reverse-phase columnchromatography, eluting with 5-55% acetonitrile/water to yield theproduct as a white solid (45 mg, 84% yield). MS (apci pos) m/z=427.1(M+H).

Example 189

1-((3S,4R)-1-(cyanomethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea Step A: Preparation oftert-butyl (3S,4R)-1-(cyanomethyl)-4-phenylpyrrolidin-3-ylcarbamate

To a solution of tert-butyl (3S,4R)-4-phenylpyrrolidin-3-ylcarbamate(535 mg, 2.04 mmol, purchased from ACS Scientific) and TEA (313 μL, 2.24mmol) in THF (8 mL) was added 2-bromoacetonitrile (156 μL, 2.24 mmol)dropwise. After stirring at ambient temperature overnight, the reactionmixture was filtered and concentrated in vacuo. The crude material waspurified by silica column chromatography, eluting with 50% hexanes/EtOActo yield the product as a white solid (510 mg, 83% yield). MS (apci pos)m/z=302.0 (M+H).

Step B: Preparation of2-((3S,4R)-3-amino-4-phenylpyrrolidin-1-yl)acetonitrile hydrochloride

A mixture of tert-butyl(3S,4R)-1-(cyanomethyl)-4-phenylpyrrolidin-3-ylcarbamate (490 mg, 1.63mmol) and HCl (20 mL, 80 mmol, 4 N dioxane) was stirred at ambienttemperature for 2 hours. The reaction was concentrated in vacuo,triturated with ether and dried on high vacuum to yield a pale-yellowishsolid. LCMS showed this to be a mixture of two products:2-((3S,4R)-3-amino-4-phenylpyrrolidin-1-yl)acetonitrile hydrochlorideand 2-((3S,4R)-3-amino-4-phenylpyrrolidin-1-yl)acetamide hydrochloridein approximately a 1:2 ratio; MS (apci pos) m/z=202.1 and 220.1 (M+H),respectively. This mixture of the two products was used directly in thenext step without further purification.

Step C: Preparation of1-((3S,4R)-1-(cyanomethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

To a clear solution of the crude product from Step B (39 mg, 0.16 mmol)in DMA (420 μL, 0.13 mmol) was added phenyl2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (40 mg,0.13 mmol), followed by DIEA (110 μL, 0.63 mmol) at ambient temperatureand the reaction mixture was stirred for 18 hours. The reaction mixturewas directly purified by reverse-phase column chromatography, elutingwith 5-54% acetonitrile/water to yield the title product as a whitesolid (11 mg, 21% yield). MS (apci pos) m/z=427.1 (M+H).

Example 190

2-((3R,4S)-3-phenyl-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureido)pyrrolidin-1-yl)acetamide

To a clear solution of the crude product from Example 189, Step Bcontaining 2-((3S,4R)-3-amino-4-phenylpyrrolidin-1-yl)acetamidehydrochloride (39 mg, 0.16 mmol) in DMA (420 μL, 0.13 mmol) was addedphenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (40mg, 0.13 mmol), followed by DIEA (110 μL, 0.63 mmol) at ambienttemperature, and the reaction mixture was stirred for 18 hours. Thereaction mixture was directly purified by reverse-phase columnchromatography, eluting with 5-54% acetonitrile/water to yield the titleproduct as a white solid (20 mg, 36% yield). MS (apci pos) m/z=445.1(M+H).

Example 191

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-hydroxyethyl)pyrrolidin-3-yl)-3-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)ureaStep A: Preparation of tert-butyl(3S,4R)-4-(3,4-difluorophenyl)-1-(2-hydroxyethyl)pyrrolidin-3-ylcarbamate

Tert-butyl (3S,4R)-4-(3,4-difluorophenyl)pyrrolidin-3-ylcarbamate (ACSScientific, 410 mg, 1.37 mmol), 2-bromoethanol (180 mg, 1.44 mmol) andDIEA (533 mg, 4.12 mmol) were combined in 1 mL of DMF and stirred atambient temperature for 72 hours. The reaction mixture was directlypurified by reverse-phase column chromatography, eluting with 0-50%acetonitrile/water to afford the title compound (290 mg, 61.6% yield).MS (apci) m/z=343.0 (M+H).

Step B: Preparation of2-((3S,4R)-3-amino-4-(3,4-difluorophenyl)pyrrolidin-1-yl)ethanolhydrochloride

Tert-butyl (3S,4R)-4-(3,4-difluorophenyl)-1-(2-hydroxyethyl)pyrrolidin-3-ylcarbamate (230 mg, 0.672 mmol) and hydrogen chloride inisopropanol (480 μL, 3.36 mmol) were combined and stirred at ambienttemperature for 5 hours. The reaction was concentrated to afford thetitle compound (166 mg, 102% yield). MS (apci) m/z=243.0 (M+H).

Step C: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-hydroxyethyl)pyrrolidin-3-yl)-3-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)urea

2-((3S,4R)-3-Amino-4-(3,4-difluorophenyl)pyrrolidin-1-yl)ethanolhydrochloride (160 mg, 0.574 mmol), phenyl3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate (168 mg, 0.547 mmol) andDIEA (286 μL, 1.64 mmol) were combined in 0.5 mL of DMF and stirred atambient temperature for 1 hour. The reaction was directly purified byreverse-phase column chromatography, eluting with 0-50%acetonitrile/water, to afford the title compound (127 mg, 51.0% yield).MS (apci) m/z=456.0 (M+H).

Example 192

1-((trans)-1-(3,3,4,4,4-pentafluorobutyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

1-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-((trans)-4-phenylpyrrolidin-3-yl)urea(Example 182, Step B, 8.0 mg, 0.021 mmol),1,1,1,2,2-pentafluoro-4-iodobutane (5.7 mg, 0.021 mmol) and DIEA (3.6μL, 0.021 mmol) were combined in 0.1 mL of DMF and stirred at 60° C. for2 hours. The reaction was directly purified by reverse-phase columnchromatography, eluting with 0-65% acetonitrile/water to afford thetitle compound (3.2 mg, 29% yield). MS (apci) m/z=534.1 (M+H).

Example 193

1-((trans)-1-ethyl-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

1-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-((trans)-4-phenylpyrrolidin-3-yl)urea(Example 182, Step B, 5.0 mg, 0.012 mmol), bromoethane (1.3 mg, 0.012mmol) and DIEA (4.1 μL, 0.024 mmol) were combined in 0.1 mL of DMF andstirred at ambient temperature for 4 hours. The reaction was directlypurified by reverse-phase column chromatography, eluting with 0-65%acetonitrile/water to afford the title compound (4.3 mg, 88% yield). MS(apci) m/z=416.1 (M+H).

Example 194

1-((trans)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea Step A: Preparation oftert-butyl (trans)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate

Trans-tert-butyl-4-phenylpyrrolidin-3-ylcarbamate (1.00 g, 3.81 mmol),2,2,2-trifluoroethyl trifluoromethanesulfonate (1.06 g, 4.57 mmol) andDIEA (1.48 g, 11.4 mmol) were combined in 2 mL of DMF and stirred atambient temperature for 1 hour. The reaction was directly purified byreverse-phase column chromatography, eluting with 0-75%acetonitrile/water to afford the title compound (1.19 g, 90.7% yield).MS (apci) m/z=345.0 (M+H).

Step B: Preparation of(trans)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-aminehydrochloride

Tert-butyl (trans)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (1.19 g, 3.46 mmol) and HCl (5 N in isopropanol, 1.48 mL, 10.4mmol) were combined and stirred at ambient temperature for 5 hours. Thereaction was concentrated to provide the title compound (0.85 g, 101%yield). MS (apci) m/z=245.0 (M+H).

Step C: Preparation of1-((trans)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

(trans)-4-Phenyl-1-(2,2,2-trifluoro-ethyl)pyrrolidin-3-aminehydrochloride (10.0 mg, 0.0356 mmol), phenyl2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (9.48 mg,0.0297 mmol) and DIEA (15.5 μL, 0.0891 mmol) were combined in 0.2 mL ofDMF and stirred at ambient temperature for 1 hour. The reaction wasdirectly purified by reverse-phase column chromatography, eluting with0-75% acetonitrile/water, to afford the title compound (11.5 mg, 82.5%yield). MS (apci) m/z=470.0 (M+H).

Example 195

1-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)-3-((trans)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea

Prepared by the method as described in Example 194, substituting phenyl3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate for phenyl2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate in Step C.The material was purified by reverse-phase column chromatography elutingwith 0-70% acetonitrile/H₂O to provide the title compound (6.5 mg, 48%yield). MS (apci) m/z=458.1 (M+H).

Example 196

1-(3-(2-methoxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((trans)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea

Prepared by the method as described in Example 194, substituting phenyl3-(2-methoxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate forphenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate inStep C. The material was purified by reverse-phase column chromatographyeluting with 0-70% acetonitrile/H₂O to provide the title compound (9.3mg, 61% yield). MS (apci) m/z=518.1 (M+H).

Example 197

1-((trans)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

Prepared by the method as described in Example 194, Steps A-C, usingtert-butyl (3S,4R)-4-phenylpyrrolidin-3-ylcarbamate, (purchased from ACSScientific, catalog #3-1005) instead oftrans-tert-butyl-4-phenylpyrrolidin-3-ylcarbamate in Step A. The finalproduct was purified by reverse-phase column chromatography eluting with0-60% acetonitrile/H₂O to provide the title compound (7.2 mg, 52%yield). MS (apci) m/z=470.0 (M+H).

Example 198

1-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea

Prepared by the method as described in Example 197, substituting phenyl3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate for phenyl 2-phenyl-2,4,5,6-tetrahydro-cyclopenta[c]pyrazol-3-ylcarbamate in Step C. Thematerial was purified by reverse-phase column chromatography elutingwith 0-60% acetonitrile/H₂O to provide the title compound (10.0 mg,67.5% yield for the urea formation). MS (apci) m/z=458.0 (M+H).

Example 199

1-(3-(2-methoxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea

Prepared by the method as described in Example 197, substituting phenyl3-(2-methoxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate forphenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate.The material was purified by reverse-phase column chromatography elutingwith 0-70% acetonitrile/H₂O to provide the title compound (8.9 mg, 53%yield). MS (apci) m/z=518.1 (M+H).

Example 200

1-((3S,4R)-4-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

Prepared by the method as described in Example 194, Step A-C usingtert-butyl (3S,4R)-4-(3-fluorophenyl)pyrrolidin-3-ylcarbamate (purchasedfrom ACS Scientific, catalog #3-1029) instead oftrans-tert-butyl-4-phenylpyrrolidin-3-ylcarbamate in Step A. The finalproduct was purified by reverse-phase column chromatography eluting with0-75% acetonitrile/H₂O to provide the title compound (12 mg, 92% yield).MS (apci) m/z=488.1 (M+H).

Example 201

1-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea

Prepared by the method as described in Example 200, substituting phenyl3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate for phenyl2-phenyl-2,4,5,6-tetrahydro-cyclopenta[c]pyrazol-3-ylcarbamate in StepC. The material was purified by reverse-phase column chromatographyeluting with 5-80% acetonitrile/H₂O to provide the title compound (5.3mg, 48% yield). MS (apci) m/z=476.0 (M+H).

Example 202

1-((3S,4R)-4-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(3-(2-methoxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared by the method as described in Example 200, substituting phenyl3-(2-methoxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate forphenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate.The material was purified by reverse-phase column chromatography elutingwith 5-80% acetonitrile/H₂O to provide the title compound (6.6 mg, 58%yield). MS (apci) m/z=536.1 (M+H).

Example 203

1-((3S,4R)-4-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(1-methyl-3-phenyl-1H-pyrazol-5-yl)urea

Prepared by the method as described in Example 200, substituting phenyl1-methyl-3-phenyl-1H-pyrazol-5-ylcarbamate for phenyl2-phenyl-2,4,5,6-tetrahydro-cyclopenta[c]pyrazol-3-ylcarbamate. Thematerial was purified by reverse-phase column chromatography elutingwith 0-75% acetonitrile/H₂O to provide the title compound (6.3 mg, 64%yield). MS (apci) m/z=462.0 (M+H).

Example 204

1-((3R,4S)-4-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureaStep A: Preparation of (E)-3-(4-chloro-3-fluorophenyl)acryloyl chloride

(E)-3-(4-chloro-3-fluorophenyl)acrylic acid (28.1 g, 140 mmol) wassuspended in chloroform (250 mL) and DMF (0.1 mL) was added followed byoxalyl chloride (20.0 mL, 229 mmol). The reaction was stirred for 18hours and then evaporated to dryness. Heptane was added and the mixturewas concentrated to afford the product (30.6 g, 99.7% yield) as paleyellow solid.

Step B: Preparation of(R)-4-benzyl-3-((3R,4S)-1-benzyl-4-(4-chloro-3-fluorophenyl)pyrrolidine-3-carbonyl)oxazolidin-2-one

(R)-4-benzyloxazolidin-2-one (21.8 g, 123 mmol) was dissolved in THF(600 mL) and cooled to −78° C. Lithium bis(trimethylsilyl)amide in THF(127 mL, 127 mmol) was added dropwise over 15 minutes and the mixturewas stirred for another 15 minutes at −78° C. A solution of(E)-3-(4-chloro-3-fluorophenyl)acryloyl chloride (28.3 g, 129 mmol) inTHF (100 mL) was added and the mixture stirred for 1 hour at −78° C.,then allowed to warm to ambient temperature and stirred for anotherhour. Saturated aqueous sodium bicarbonate solution (50 mL) was addedand the reaction was stirred for 1 hour. Then THF was removed in vacuo,ethyl acetate (1 L) was added and the reaction mixture was washed withwater (2×) and brine, dried with MgSO₄, filtered and evaporated to give(R,E)-4-benzyl-3-(3-(4-chloro-3-fluorophenyl)acryloyl)oxazolidin-2-one(44.3 g, 100% yield) as tan solid. The solid was dissolved in toluene(500 mL) and 2,2,2-trifluoroacetic acid (0.9486 mL, 12.31 mmol) wasadded. The temperature was warmed to 35° C. andN-benzyl-1-methoxy-N-((trimethylsilyl) methyl)methanamine (52.50 mL,184.7 mmol) was added over 20 minutes, keeping the temperature at 25-30°C. with an external water bath. The mixture was washed with saturatedaqueous sodium bicarbonate solution and water and concentrated in vacuoto obtain an oily residue that was triturated with hexanes, filtered andwashed with hexanes to obtain a white solid (55.7 g). This solid (55.7g) was suspended in hexanes (200 mL) and heated to reflux. Benzene (220mL) was added until the solid dissolved at reflux. The solution wasallowed to slowly cool to ambient temperature and then placed intofreezer for 4 hours. The resulting solid was collected by filtration andwashed with 100 mL of cold 1:1 hexane/benzene. The resultant solid (7.6g) was purified by silica column chromatography eluting with 20-40%EtOAc/Hexanes.(R)-4-benzyl-3-((3S,4R)-1-benzyl-4-(4-chloro-3-fluorophenyl)pyrrolidine-3-carbonyl)oxazolidin-2-one(3.2 g, 42% yield) eluted first followed by(R)-4-benzyl-3-((3R,4S)-1-benzyl-4-(4-chloro-3-fluorophenyl)pyrrolidine-3-carbonyl)oxazolidin-2-one(3.0 g, 39% yield). MS (apci) m/z=493.0 (M+H).

Step C: Preparation of(3R,4S)-1-benzyl-4-(4-chloro-3-fluorophenyl)pyrrolidine-3-carboxylicacid

Hydrogen peroxide (30% aqueous, 2.38 mL, 23.1 mmol) was added dropwiseto a mixture of lithium hydroxide monohydrate (0.638 g, 15.2 mmol) andice-water (50 g). The mixture was stirred for 30 minutes and theresultant solution was added to solution of(R)-4-benzyl-3-((3R,4S)-1-benzyl-4-(4-chloro-3-fluorophenyl)pyrrolidine-3-carbonyl)oxazolidin-2-one(3.00 g, 6.09 mmol) in THF (50 mL). The reaction was stirred at ambienttemperature for 5 hours, quenched by addition of 2M aqueous Na₂SO₃ (20mL) and agitated overnight. The pH was adjusted to 6 with solid KHSO₄and the mixture was extracted with EtOAc (2×100 mL). The combinedorganic extracts were washed with brine, dried with MgSO₄, filtered andconcentrated in vacuo. The residue was purified by silica columnchromatography eluting with 10% MeOH/DCM to provide the product (1.80 g,88.6% yield) as white solid. MS (apci) m/z=334.0 (M+H).

Step D: Preparation of tert-butyl(3R,4S)-1-benzyl-4-(4-chloro-3-fluorophenyl) pyrrolidin-3-ylcarbamate

(3R,4S)-1-benzyl-4-(4-chloro-3-fluorophenyl) pyrrolidine-3-carboxylicacid (120 mg, 0.360 mmol), NEt₃ (150 μL, 1.08 mmol), anddiphenylphosphoryl azide (116 μL, 0.539 mmol) were combined in 2 mL ofToluene in a sealed vessel and stirred at 100° C. for 30 minutes. Thereaction was allowed to cool to ambient temperature and lithium2-methylpropan-2-olate in THF (1.44 mL, 0.719 mmol) was added. Thereaction was stirred at 100° C. for 5 hours, cooled, concentrated andpurified by reverse-phase column chromatography eluting with 20-90%acetonitrile/H₂O to afford the product (61.0 mg, 41.9% yield). MS (apci)m/z=405.0 (M+H).

Step E: Preparation of tert-butyl(3R,4S)-4-(3-fluorophenyl)pyrrolidin-3-ylcarbamate

Tert-butyl(3R,4S)-1-benzyl-4-(4-chloro-3-fluorophenyl)pyrrolidin-3-ylcarbamate (60mg, 0.15 mmol) was dissolved in 5 mL of MeOH and 10% Pd/C (32 mg, 0.030mmol) was added. The reaction was stirred under a hydrogen-filledballoon for 18 hours, filtered through Celite®, and then concentrated toafford the title compound (36 mg, 87% yield). MS (apci) m/z=281.1 (M+H).

Step F: Preparation of tert-butyl(3R,4S)-4-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate

Tert-butyl (3R,4S)-4-(3-fluorophenyl)pyrrolidin-3-ylcarbamate (35 mg,0.12 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (38 mg, 0.16mmol) and DIEA (65 μL, 0.37 mmol) were combined in 0.5 mL of DMF andstirred at ambient temperature for 18 hours. The reaction was directlypurified by reverse-phase column chromatography eluting with 0-80%acetonitrile/H₂O to afford the product (30 mg, 66% yield). MS (apci)m/z=363.0 (M+H).

Step G: Preparation of(3R,4S)-4-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-aminehydrochloride

Tert-butyl(3R,4S)-4-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate(30 mg, 0.083 mmol) and hydrogen chloride in isopropanol (50 μL, 0.25mmol) were combined in 1 mL of isopropanol and stirred at ambienttemperature for 4 hours. The reaction was concentrated in vacuo toafford the product (21 mg, 97% yield). MS (apci) m/z=263.0 (M+H).

Step H: Preparation of1-((3R,4S)-4-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

(3R,4S)-4-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-amine(10.0 mg, 0.0381 mmol), phenyl2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (10.1 mg,0.0318 mmol) and DIEA (16.6 μL, 0.0953 mmol) were combined in 0.2 mL ofDMF and stirred at ambient temperature for 18 hours. The reaction waspurified by reverse-phase column chromatography eluting with 0-70%acetonitrile/H₂O to provide the title compound (12.5 mg, 80.7% yield).MS (apci) m/z=488.1 (M+H).

Example 205

1-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea

Prepared by the method as described in Example 204, Step H, substitutingphenyl 3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate for phenyl2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate. Thematerial was purified by reverse-phase column chromatography elutingwith 0-80% acetonitrile/H₂O to provide the title compound (9.3 mg, 58%yield). MS (apci) m/z=476.0 (M+H).

Example 206

1-((trans)-1-(1,3-difluoropropan-2-yl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureaStep A: Preparation of tert-butyl(trans)-1-(1,3-difluoropropan-2-yl)-4-phenyl-pyrrolidin-3-ylcarbamate

1,3-Difluoropropan-2-ol (150.0 mg, 1.561 mmol) was dissolved in DCM (5mL) and the solution was cooled to 0° C. DIEA (339.9 μL, 1.952 mmol) wasadded followed by trifluoromethanesulfonic anhydride (197.0 μL, 1.171mmol). The reaction was stirred at 0° C. for 1 hour andtert-butyl-4-phenylpyrrolidin-3-ylcarbamate (102.4 mg, 0.3903 mmol) wasadded. The reaction was allowed to warm to ambient temperature over 2hours, concentrated, loaded onto a samplet using MeOH, and purified byreverse-phase column chromatography eluting with 0-70% acetonitrile/H₂Oto afford the product (119.0 mg, 89.56% yield). MS (apci) m/z=341.1(M+H).

Step B: Preparation of(trans)-1-(1,3-difluoropropan-2-yl)-4-phenylpyrrolidin-3-aminehydrochloride

Tert-butyl(trans)-1-(1,3-difluoropropan-2-yl)-4-phenylpyrrolidin-3-ylcarbamate(119 mg, 0.350 mmol) and hydrogen chloride (5 N in isopropanol, 210 μL,1.05 mmol) were combined in 1 mL of isopropanol and stirred at ambienttemperature for 4 hours. The reaction mixture was concentrated in vacuoto afford the product (85.0 mg, 101% yield). MS (apci) m/z=241.1 (M+H).

Step C: Preparation of1-((trans)-1-(1,3-difluoropropan-2-yl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

(trans)-1-(1,3-Difluoropropan-2-yl)-4-phenylpyrrolidin-3-aminehydrochloride (10.0 mg, 0.0361 mmol), phenyl2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (9.62 mg,0.0301 mmol) and DIEA (15.7 μL, 0.0903 mmol) were combined in 0.2 mL ofDMF and stirred at ambient temperature for 18 hours. The reactionmixture was purified by reverse-phase column chromatography eluting with0-70% acetonitrile/H₂O to provide the product (11.3 mg, 80.6% yield). MS(apci) m/z=466.1 (M+H).

Example 207

(trans)-tert-butyl 3-(3-methoxyphenyl)-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureido)pyrrolidine-1-carboxylateStep A: Preparation of tert-butyl(trans)-1-(1,3-difluoropropan-2-yl)-4-phenylpyrrolidin-3-ylcarbamate

Trans-tert-butyl 3-amino-4-(3-methoxyphenyl) pyrrolidine-1-carboxylate(100.0 mg, 0.3420 mmol), phenyl2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (99.30 mg,0.3109 mmol) and DIEA (162.5 μL, 0.9328 mmol) were combined in 0.2 mL ofDMF and stirred at ambient temperature for 1 hour. The reaction mixturewas purified by reverse-phase column chromatography eluting with 0-80%acetonitrile/H₂O to afford the product (102.0 mg, 63.38% yield). MS(apci) m/z=518.1 (M+H).

Step B: Preparation of1-((trans)-4-(3-methoxyphenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureahydrochloride

(Trans)-tert-butyl 3-(3-methoxyphenyl)-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureido)pyrrolidine-1-carboxylate (102 mg, 0.197 mmol) and hydrogen chloride inisopropanol (118 μL, 0.591 mmol) were combined in 1 mL of isopropanoland stirred at ambient temperature for 4 hours. The reaction wasconcentrated in vacuo to afford the product (80.0 mg, 97.2% yield). MS(apci) m/z=418.1 (M+H).

Step C: Preparation of1-((trans)-4-(3-methoxyphenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

1-((trans)-4-(3-methoxyphenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureahydrochloride (8.0 mg, 0.018 mmol), 2,2,2-trifluoroethyltrifluoromethanesulfonate (6.1 mg, 0.026 mmol) and DIEA (9.2 μL, 0.053mmol) were combined in 0.2 mL of DMF and stirred at ambient temperaturefor 1 hour. The reaction mixture was directly purified by reverse-phasecolumn chromatography eluting with 0-80% acetonitrile/H₂O to provide thetitle compound (6.7 mg, 76% yield). MS (apci) m/z=500.1 (M+H).

Example 208

1-((trans)-4-(3-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureaStep A: Preparation of (trans)-tert-butyl3-(3-chlorophenyl)-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureido)pyrrolidine-1-carboxylate

(trans)-1-(tert-Butoxy-carbonyl)-4-(3-chlorophenyl)pyrrolidine-3-carboxylicacid (150 mg, 0.460 mmol), NEt₃ (193 μL, 1.38 mmol), anddiphenylphosphoryl azide (149 μL, 0.691 mmol) were combined in 2 mL oftoluene in a sealed vessel and stirred at 100° C. for 30 minutes. Thereaction was cooled and2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine (Table 1; 183mg, 0.921 mmol) was added. The reaction mixture was stirred at 100° C.for 16 hours, cooled, concentrated and purified by reverse-phase columnchromatography eluting with 0-60% acetonitrile/H₂O to provide theproduct (42 mg, 18% yield). MS (apci) m/z=522.1 (M+H).

Step B: Preparation of1-((trans)-4-(3-chlorophenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureahydrochloride

(trans)-tert-butyl3-(3-chlorophenyl)-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureido)pyrrolidine-1-carboxylate(40 mg, 0.077 mmol) and hydrogen chloride in isopropanol (46 μL, 0.23mmol) were combined in 10.1 mL of IPA and stirred at ambient temperaturefor 12 hours. The reaction mixture was concentrated in vacuo to affordthe product (32 mg, 99% yield). MS (apci) m/z=422.0 (M+H).

Step C: Preparation of1-((trans)-4-(3-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

1-((trans)-4-(3-Chlorophenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea hydrochloride (15 mg, 0.033mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (11 mg, 0.049mmol) and DIEA (17 μL, 0.098 mmol) were combined in 0.2 mL of DMF andstirred at ambient temperature for 1 hour. The reaction mixture wasdirectly purified by reverse-phase column chromatography eluting with0-80% acetonitrile/H₂O to provide the title compound (8.2 mg, 50%yield). MS (apci) m/z=504.0 (M+H).

Example 209

1-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-((trans)-4-(pyridin-2-yl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea

Prepared by the method as described in Example 208, substituted(trans)-1-(tert-butoxycarbonyl)-4-(2-pyridyl)pyrrolidine-3-carboxylicacid for(trans)-1-(tert-butoxycarbonyl)-4-(3-chlorophenyl)pyrrolidine-3-carboxylicacid in Step A. The crude final product was purified by reverse-phasecolumn chromatography eluting with 0-60% acetonitrile/H₂O to provide thetitle compound (4.2 mg, 23% yield for 3 steps). MS (apci) m/z=471.1(M+H).

Example 210

1-((trans)-4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

Prepared by the method as described in Example 208, substituting(trans)-1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)pyrrolidine-3-carboxylicacid for(trans)-1-(tert-butoxycarbonyl)-4-(3-chlorophenyl)pyrrolidine-3-carboxylicacid in Step A. The final product was purified by reverse-phase columnchromatography eluting with 0-70% acetonitrile/H₂O to provide the titlecompound (10.0 mg, 65% yield for 3 steps). MS (apci) m/z=488.2 (M+H).

Example 211

1-((trans)-4-(4-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

Prepared by the method as described in Example 208, using(trans)-1-(tert-butoxycarbonyl)-4-(4-chlorophenyl)pyrrolidine-3-carboxylicacid instead of(trans)-1-(tert-butoxycarbonyl)-4-(3-chlorophenyl)pyrrolidine-3-carboxylicacid in Step A. The final product was purified by reverse-phase columnchromatography eluting with 0-70% acetonitrile/H₂O to provide the titlecompound (7.3 mg, 14% yield for 3 steps). MS (apci) m/z=504.2 (M+H).

Example 212

1-((trans)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

Prepared by the method as described in Example 208, substituting(trans)-1-(tert-butoxycarbonyl)-4-(2-chlorophenyl)pyrrolidine-3-carboxylicacid for(trans)-1-(tert-butoxy-carbonyl)-4-(3-chlorophenyl)pyrrolidine-3-carboxylicacid in Step A. The final product was purified by reverse-phase columnchromatography eluting with 0-70% acetonitrile/H₂O to provide the titlecompound (5.2 mg, 34% yield for 3 steps). MS (apci) m/z=504.2 (M+H).

Example 213

1-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-((trans)-4-(pyridin-3-yl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea

Prepared by the method as described in Example 208, substituting(trans)-1-(tert-butoxycarbonyl)-4-(3-pyridyl)pyrrolidine-3-carboxylicacid for(trans)-1-(tert-butoxycarbonyl)-4-(3-chlorophenyl)pyrrolidine-3-carboxylicacid in Step A. The final product was purified by reverse-phase columnchromatography eluting with 0-60% acetonitrile/H₂O to provide the titlecompound (1.2 mg, 8% yield for 3 steps). MS (apci) m/z=471.2 (M+H).

Example 214

1-((trans)-4-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

Prepared by the method as described in Example 208, substituting(trans)-1-(tert-butoxycarbonyl)-4-(2-fluorophenyl)pyrrolidine-3-carboxylicacid for(trans)-1-(tert-butoxycarbonyl)-4-(3-chlorophenyl)pyrrolidine-3-carboxylicacid in Step A. The final product was purified by reverse-phase columnchromatography eluting with 0-70% acetonitrile/H₂O to provide the titlecompound (7.7 mg, 57% yield for 3 steps). MS (apci) m/z=488.2 (M+H).

Example 215

1-((trans)-4-(4-fluorophenyl)-1-(2,2-difluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

Prepared by the method as described in Example 210, substituting2,2-difluoroethyl trifluoromethanesulfonate for 2,2,2-trifluoroethyltrifluoromethanesulfonate. The final product was purified byreverse-phase column chromatography eluting with 0-60% acetonitrile/H₂Oto provide the title compound (4.9 mg, 46% yield for the alkylation). MS(apci) m/z=471.2 (M+H).

Example 216

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureaStep A: Preparation of 4-iodo-1-(4-methoxybenzyl)-1H-pyrazole

To a solution of 4-iodo-1H-pyrazole (5.54 g, 28.6 mmol) and K₂CO₃ (4.74g, 34.3 mmol) in DMF (20 mL) was added 1-(chloromethyl)-4-methoxybenzene(4.67 mL, 34.3 mmol) and stirred at ambient temperature for 2 hours.Ether (80 mL) and water (30 mL) were added. The organic phase wasseparated, washed with brine and dried over sodium sulfate. Afterremoval of solvent, the residue was purified by silica columnchromatography eluting with 25% EtOAc/hexanes to afford the titlecompound as white solid (8.0 g, 89% yield). ¹H NMR (d6-DMSO) δ 7.97 (s,1H), 7.52 (s, 1H), 7.21 (d, 2H), 6.89 (d, 2H), 5.24 (s, 2H), 3.73 (s,3H).

Step B: Preparation of tert-butyl(3S,4R)-4-(3,4-difluorophenyl)-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrrolidin-3-ylcarbamate

A mixture of tert-butyl(3S,4R)-4-(3,4-difluorophenyl)pyrrolidin-3-ylcarbamate (ACS Scientific,522 mg, 1.75 mmol), 4-iodo-1-(4-methoxybenzyl)-1H-pyrazole (500 mg, 1.59mmol), K₂CO₃ (660 mg, 4.78 mmol), (S)-pyrrolidine-2-carboxylic acid(73.3 mg, 0.637 mmol), and Cu(I)I (60.6 mg, 0.318 mmol) were combined inDMSO (4 mL) in a sealed vessel and heated to 100° C. for 18 hours. Thereaction mixture was diluted with DCM (40 mL), washed with H₂O (2×20mL), dried (MgSO₄), filtered and concentrated. Purified by silica columnchromatography eluting with 1% MeOH/DCM to afford the title compound asa brown oil (376 mg, 49% yield). MS (apci) m/z=485.2 (M+H).

Step C: Preparation of(3S,4R)-4-(3,4-difluorophenyl)-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrrolidin-3-aminedihydrochloride

A solution of tert-butyl(3S,4R)-4-(3,4-difluorophenyl)-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrrolidin-3-ylcarbamate(376 mg, 0.776 mmol) in EtOH (2 mL) and HCl (5-6M in iPrOH) (3.10 mL,15.5 mmol) was stirred at ambient temperature for 19 hours. Concentratedunder vacuum, diluted with Et₂O (3×20 mL) and concentrated to afford theproduct as a greenish-brown solid (401 mg, 113%). MS (apci) m/z=385.2(M+H).

Step D: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

To a solution of(3S,4R)-4-(3,4-difluorophenyl)-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrrolidin-3-aminedihydrochloride (40 mg, 0.088 mmol) in DIEA (0.061 mL, 0.35 mmol) andDMA (1 mL) was added phenyl3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared as inExample 1, Step A starting with Intermediate P135; 29.5 mg, 0.088 mmol)and the reaction mixture as stirred at ambient temperature for 1 hour.The reaction mixture was directly purified by reverse-phase columnchromatography, eluting with 5-70% acetonitrile/water to afford theproduct as a white solid (24 mg, 44% yield). MS (apci) m/z=628.3 (M+H).

Step E: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

A solution of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea(22 mg, 0.035 mmol) in TFA (2 mL) was heated in a pressure tube to 60°C. for 18 hours. The reaction mixture was transferred to around-bottomed flask, concentrated and azeotroped with toluene (2×10mL). The crude product was dissolved in MeOH (5 mL), and residual TFAwas removed by passing through a polymer-supported resin (StratoSpheresPL-HCO₃ MP). The crude product was purified by preparatory TLC (0.5 mmplate, eluted 10% MeOH/DCM) to afford the title compound as an off-whitesolid (13 mg, 73% yield). MS (apci) m/z=508.2 (M+H).

Example 217

1-((3S,4R)-4-(3,5-difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the method described in Example 216, replacingtert-butyl (3S,4R)-4-(3,4-difluorophenyl)pyrrolidin-3-ylcarbamate withtert-butyl (3S,4R)-4-(3,5-difluorophenyl)pyrrolidin-3-ylcarbamate inStep B. MS (apci) m/z=508.2 (M+H).

Example 218

1-((3S,4R)-4-(3,5-difluorophenyl)-1-(1H-pyrazol-3-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-H-pyrazol-5-yl)urea

Prepared according to the method described in Example 216, replacing4-iodo-1H-pyrazole with 3-iodo-1H-pyrazole in Step A and replacingtert-butyl (3S,4R)-4-(3,4-difluorophenyl)pyrrolidin-3-ylcarbamate withtert-butyl (3S,4R)-4-(3,5-difluorophenyl) pyrrolidin-3-ylcarbamate inStep B. MS (apci) m/z=508.2 (M+H).

Example 219

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(3-methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the method described in Example 216, replacing4-iodo-1H-pyrazole with 4-iodo-3-methyl-1H-pyrazole in Step A. MS (apci)m/z=522.2 (M+H).

Example 220

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(3-(trifluoromethyl)-1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the method described in Example 216, replacing4-iodo-1H-pyrazole with 4-iodo-3-methyl-1H-pyrazole in Step A. MS (apci)m/z=576.2 (M+H).

Example 221

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-((S)-2-hydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureaStep A: Preparation of1-(3-((S)-2-(tert-butyldimethylsilyloxy)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrrolidin-3-yl)urea

To a solution of(3S,4R)-4-(3,4-difluorophenyl)-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrrolidin-3-aminedihydro-chloride (Example 216, Step C, 35 mg, 0.077 mmol) in DIEA (0.053mL, 0.31 mmol) and DMA (1 mL) was added (S)-phenyl3-(2-(tert-butyldimethylsilyloxy)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate(prepared as in Example 1, Step A starting with Intermediate P211; 37mg, 0.077 mmol) and the reaction mixture as stirred at ambienttemperature for 1 hour. The reaction mixture was directly purified byreverse-phase column chromatography, eluting with 5-95%acetonitrile/water to afford the product as a white solid (40 mg, 68%yield). MS (apci) m/z=772.4 (M+H).

Step B: Preparation of(S)-1-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yloxy)propan-2-yl2,2,2-trifluoro acetate

A solution of 1-(3-((S)-2-(tert-butyldimethylsilyloxy)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrrolidin-3-yl)urea(39 mg, 0.051 mmol) in TFA (2 mL) was heated in a pressure tube to 60°C. for 16 hours. The reaction mixture was transferred to around-bottomed flask, concentrated and azeotroped with toluene (2×10 mL)to afford the product as a tan solid (32 mg, 99%). MS (apci) m/z=634.2(M+H).

Step C: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-((S)-2-hydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

To a solution of(S)-1-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yloxy)propan-2-yl2,2,2-trifluoroacetate (32 mg, 0.051 mmol) in MeOH (1 mL) and THF (2 mL)was added 2M aqueous LiOH (0.5 mL, 1.0 mmol). The reaction was stirredat ambient temperature for 3 hours, diluted with H₂O (20 mL), extracted10:90 MeOH/DCM (2×20 mL) and the combined organic phases were dried(MgSO₄), filtered and concentrated under reduced pressure. Purified bysilica column chromatography eluting with 10% MeOH/DCM to afford thetitle compound as a white solid (19 mg, 72% yield). MS (apci) m/z=538.2(M+H).

Example 222

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-((R)-2,3-dihydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the method described in Example 221 replacing(S)-phenyl3-(2-(tert-butyldimethylsilyloxy)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarba-matewith (S)-phenyl3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate(prepared as in Example 1, Step A starting with Intermediate P209) inStep A. MS (apci) m/z=554.2 (M+H).

The compounds in the following table were prepared according to themethod of Example 216, substituting the appropriate starting material inSteps A and B and substituting the appropriate pyrazole intermediate inStep D.

Ex. # Structure Name MS (apci) m/z 223

1-((3S,4R)-4-(3,5-difluoro- phenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3,4- dimethyl-1-phenyl-1H-pyrazol- 5-yl)urea478.2 (M + H) 224

1-((3S,4R)-(3,4- difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3,4- dimethyl-1-phenyl-1H-pyrazol- 5-yl)urea478.2 (M + H) 225

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-(3- methoxypropyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea 536.3 (M + H) 226

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-(2- methoxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea 538.2 (M + H) 227

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-(2- hydroxy-2-methylpropoxy)-4-methyl-1-phenyl-1H-pyrazol-5- yl)urea 552.2 (M + H) 228

1-(3-ethoxy-4-methyl-1-phenyl- 1H-pyrazol-5-yl)-3-((3S,4R)-1-(1-methyl-1H-pyrazol-5-yl)-4- phenylpyrrolidin-3-yl)urea 486.3 (M + H)229

1-(3-ethoxy-4-methyl-1-phenyl- 1H-pyrazol-5-yl)-3-((3R,4S)-1-(1-methyl-1H-pyrazol-5-yl)-4- phenylpyrrolidin-3-yl)urea 486.3 (M + H)230

1-((3S,4R)-4-(3,5- difluorophenyl)-1-(1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-yl)-3- (3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea 522.2 (M + H) 231

1-((3R,4S)-4-(3,5- difluorophenyl)-1-(1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-yl)-3- (3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea 522.2 (M + H) 232

1-((3S,4R)-4-(3,4- difluorophenyl)-1- phenylpyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H- pyrazol-5-yl)urea 518.2 (M + H) 233

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyphenyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl- 1H-pyrazol-5-yl)urea 548.3 (M + H) 234

1-(3-ethoxy-4-methyl-1-phenyl- 1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-fluorophenyl)-4- phenylpyrrolidin-3-yl)urea 500.2 (M + H) 235

1-(3-ethoxy-4-methyl-1-phenyl- 1H-pyrazol-5-yl)-3-((3S,4R)-1-(4-fluorophenyl)-4- phenylpyrrolidin-3-yl)urea 500.2 (M + H) 236

1-(3-ethoxy-4-methyl-1-phenyl- 1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methylphenyl)-4- phenylpyrrolidin-3-yl)urea 496.3 (M + H) 237

1-(3-ethoxy-4-methyl-1-phenyl- 1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyphenyl)-4- phenylpyrrolidin-3-yl)urea 512.3 (M + H) 238

1-(3-ethoxy-4-methyl-1-phenyl- 1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-chlorophenyl)-4- phenylpyrrolidin-3-yl)urea 516.3 (M + H) 239

1-(3-ethoxy-4-methyl-1-phenyl- 1H-pyrazol-5-yl)-3-((3S,4R)-4-phenyl-1-(2- (trifluoromethoxy)phenyl)pyrrolidin- 3-yl)urea 566.2 (M +H) 240

1-((3S,4R)-1-(2,6- difluorophenyl)-4- phenylpyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H- pyrazol-5-yl)urea 566.2 (M + H) 241

1-(3-ethoxy-4-methyl-1-phenyl- 1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxypyridin-4-yl)-4- phenylpyrrolidin-3-yl)urea 487.2 (M + H) 242

1-(3-ethoxy-4-methyl-1-phenyl- 1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxypyridin-3-yl)-4- phenylpyrrolidin-3-yl)urea 513.3 (M + H) 243

1-(3-ethoxy-4-methyl-1-phenyl- 1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-ethoxypyridin-3-yl)-4- phenylpyrrolidin-3-yl)urea 527.2 (M + H) 244

1-(1′,4-dimethyl-1-phenyl- 1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-1-(2-methoxypyridin- 3-yl)-4-phenylpyrrolidin-3- yl)urea 513.2(M + H) 245

1-((3S,4R)-1-(2- methoxypyridin-3-yl)-4- phenylpyrrolidin-3-yl)-3-(4-methyl-1,3-diphenyl-1H- pyrazol-5-yl)urea 545.3 (M + H) 246

1-(4-bromo-1′-methyl-1-phenyl- 1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-1-(2-methoxypyridin- 3-yl)-4-phenylpyrrolidin-3- yl)urea 613.2(M + H) 247

1-(4-bromo-1,3-diphenyl-1H- pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxypyridin-3-yl)-4- phenylpyrrolidin-3-yl)urea 611.2 (M + H)

Example 248

1-((3S,4R)-1-((1,2,3-thiadiazol-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-vyl)ureaStep A: Preparation of tert-butyl((3S,4R)-1-((1,2,3-thiadiazol-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)carbamate

Tert-butyl (3S,4R)-4-(3,4-difluorophenyl)pyrrolidin-3-ylcarbamate (150mg, 0.503 mmol), 1,2,3-thiadiazole-4-carbaldehyde (68.9 mg, 0.603 mmol)and DIEA (186 μL, 1.01 mmol) were combined in 1 mL of DCM and stirred atambient temperature for 30 minutes. Sodium triacetoxyborohydride (213mg, 1.01 mmol) was added and the reaction was stirred at ambienttemperature overnight and concentrated. The crude material was purifiedby reverse-phase column chromatography, eluting with 0-50%acetonitrile/water to afford the product (168 mg, 0.424 mmol, 84.3%yield). MS (apci) m/z=397.1 (M+H).

Step B: Preparation of(3S,4R)-1-((1,2,3-thiadiazol-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-aminedihydrochloride

tert-butyl(3S,4R)-1-((1,2,3-thiadiazol-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-ylcarbamate(150 mg, 0.378 mmol) and 5N HCl in IPA (378 μl, 1.89 mmol) were combinedin 1 mL of IPA and left to stand at ambient temperature overnight. Thereaction was concentrated to afford the product (140 mg, 0.379 mmol,100% yield). MS (apci) m/z=297.0 (M+H).

Step C: Preparation of1-((3S,4R)-1-((1,2,3-thiadiazol-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-vyl)urea

(3S,4R)-1-((1,2,3-thiadiazol-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-aminedihydrochloride (20 mg, 0.054 mmol), phenyl2-phenyl-2,4,5,6-tetrahydro-cyclopenta[c]pyrazol-3-ylcarbamate (16 mg,0.049 mmol, prepared as described for Example 38, step E) and DIEA (26μl, 0.15 mmol) were combined in 0.2 mL of DMF and stirred at ambienttemperature for 1 hour. The reaction was loaded onto a samplet andpurified by reverse-phase column chromatography, eluting with 0-80%acetonitrile/water, to afford the title compound (24 mg, 0.046 mmol, 93%yield). MS (apci) m/z=522.2 (M+H).

Example 249

1-((3S,4R)-1-((1,2,3-thiadiazol-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared by the method as described in Example 216, Step C using phenyl3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (which was preparedaccording to the method of Example 1, Step A, starting with IntermediateP135) instead of phenyl2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate. Thematerial was purified by reverse-phase column chromatography using 0-80%acetonitrile/H₂O as the eluent to provide the title compound (23 mg,0.043 mmol, 87% yield). MS (apci) m/z=540.2 (M+H).

Example 250

1-((3S,4R)-1-((1,2,3-thiadiazol-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(3-(cyanomethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared by the method as described in Example 216, Step C, using phenyl3-(cyanomethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate instead ofphenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate.The material was purified by reverse-phase column chromatography using0-80% acetonitrile/H₂O as the eluent to provide the title compound (3.4mg, 0.0062 mmol, 50% yield). MS (apci) m/z=551.2 (M+H).

Example 251

1-((3S,4R)-1-((1,2,3-thiadiazol-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)urea

Prepared by the method as described in Example 216, Step C, using phenyl1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-ylcarbamate (9.2 mg,0.025 mmol) instead of phenyl2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate. Thematerial was purified by reverse-phase column chromatography using 0-70%acetonitrile/H₂O as the eluent to provide the title compound (4.2 mg,0.0073 mmol, 30% yield). MS (apci) m/z=576.2 (M+H).

Example 252

1-((3S,4R)-1-((1,2,3-thiadiazol-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(4-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-phenyl-1H-pyrazol-5-yl)urea

Prepared by the method as described in Example 216, Step C, using1-methyl-4-(4-methyl-5-(phenoxycarbonylamino)-1-phenyl-1H-pyrazol-3-yl)-3-(phenoxycarbonyl)-1H-imidazol-3-iumchloride instead of phenyl2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate and addingan extra equivalent of(3S,4R)-1-((1,2,3-thiadiazol-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-aminedihydrochloride. The material was purified by reverse-phase columnchromatography using 0-80% acetonitrile/H₂O as the eluent to provide thetitle compound (6.2 mg, 0.011 mmol, 42% yield). MS (apci) m/z=576.2(M+H).

Example 253

1-((3S,4R)-4-(3,4-difluorophenyl)-1-((1-methyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

Prepared by the method as described in Example 216, using1-methyl-1H-1,2,3-triazole-4-carbaldehyde instead of1,2,3-thiadiazole-4-carbaldehyde in Step A. The final product waspurified by reverse-phase column chromatography using 0-80%acetonitrile/H₂O as the eluent to provide the title compound (17 mg,0.033 mmol, 76% yield for 3 steps). MS (apci) m/z=519.2 (M+H).

Example 254

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1,3-dimethoxypropan-2-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared by the method as described in Example 249, using1,3-dimethoxypropan-2-one instead of 1,2,3-thiadiazole-4-carbaldehyde inStep A. The final product was purified by reverse-phase columnchromatography using 5-80% acetonitrile/H₂O as the eluent to provide thetitle compound (17.3 mg, 0.0318 mmol, 57.4% yield for 3 steps). MS(apci) m/z=544.3 (M+H).

Example 255

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1-methoxypropan-2-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared by the method as described in Example 249, using1-methoxypropan-2-one instead of 1,2,3-thiadiazole-4-carbaldehyde inStep A. The final product was purified by reverse-phase columnchromatography using 0-80% acetonitrile/H₂O as the eluent to provide thetitle compound (8.2 mg, 0.016 mmol, 70.1% yield for 3 steps). MS (apci)m/z=514.3 (M+H).

Example 256

1-((trans)-4-(4-fluorophenyl)-1-(2-(methylamino)ethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

1-((3S,4R)-4-(4-fluorophenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydro-cyclopenta[c]pyrazol-3-yl)ureahydrochloride (11 mg, 0.0249 mmol, prepared as for Example 210),2-iodo-N-methyl-N-tritylethanamine (19.1 mg, 0.0448 mmol) and DIEA (9.65mg, 0.0747 mmol) were combined in 0.2 mL of DMF and stirred at ambienttemperature overnight. HCl (7N in IPA, 35.6 μL, 0.249 mmol) was addedand the reaction was stirred at ambient temperature for 4 hours. 1N NaOH(2 mL) was added and the reaction was extracted with several portions ofDCM in a phase separator frit. The combined organic extracts wereconcentrated and purified by reverse-phase column chromatography using0-60% acetonitrile/H₂O as the eluent to provide the title compound (2.2mg, 0.00476 mmol, 19.1% yield). MS (apci) m/z=463.3 (M+H).

Example 257

1-((trans)-1-((1H-imidazol-2-yl)methyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

1-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-((trans)-4-phenyl-pyrrolidin-3-yl)urea(15 mg, 0.039 mmol, prepared as described in Example 182, Step B),2-(chloromethyl)-1H-imidazole hydrochloride (5.9 mg, 0.039 mmol) andDIEA (14 μL, 0.077 mmol) were combined in 0.2 mL of DMF and stirred atambient temperature for 30 minutes. The reaction was loaded onto asamplet and purified by reverse-phase column chromatography using 0-70%acetonitrile/H₂O as the eluent to provide the title compound (7.9 mg,0.017 mmol, 44% yield). MS (apci) m/z=468.2 (M+H).

Example 258

methyl3-methoxy-2-((trans)-3-phenyl-4-(3-(2-phenyl-2,4,56-tetrahydrocyclopenta[c]pyrazol-3-yl)ureido)pyrrolidin-1-yl)propanoate

1-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-((trans)-4-phenyl-pyrrolidin-3-yl)urea(30 mg, 0.077 mmol, prepared as described in Example 182, Step B),methyl 2-bromo-3-methoxypropanoate (15 mg, 0.077 mmol) and DIEA (29 μL,0.15 mmol) were combined in 0.2 mL of DCM and stirred at ambienttemperature for 3 days. The reaction was loaded onto a samplet andpurified by reverse-phase column chromatography using 5-80%acetonitrile/H₂O as the eluent to provide the title compound (24 mg,0.048 mmol, 62% yield) as a mixture of diastereomers. MS (apci)m/z=504.3 (M+H).

Example 259

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1-methoxypropan-2-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared by the method as described in Example 194, substituting methyl2-bromo-3-methoxypropanoate for 2,2,2-trifluoroethyltrifluoromethanesulfonate and stirring for 3 days instead of 1 hour inStep A. The final product was purified by reverse-phase columnchromatography using 5-80% acetonitrile/H₂O as the eluent to provide thetitle compound (260 mg, 0.482 mmol, 83.5% yield for 3 steps) as amixture of diastereomers. MS (apci) m/z=540.3 (M+H).

Example 260

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1-hydroxy-3-methoxypropan-2-yl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

Methyl2-((3R,4S)-3-(3,4-difluorophenyl)-4-(3-(2-phenyl-2,4,5,6-tetrahydro-cyclopenta[c]pyrazol-3-yl)ureido)pyrrolidin-1-yl)-3-methoxypropanoate(200 mg, 0.371 mmol, prepared as described in Example 259) was dissolvedin 5 mL of THF and the solution was cooled to 0° C. LiAlH₄ (28.1 mg,0.741 mmol) was added and the reaction was allowed to warm to ambienttemperature over 2 hours. Sodium sulfate decahydrate (1194 mg, 3.71mmol) was added and the reaction was stirred at ambient temperature for2 hours, filtered and concentrated. The crude product was purified byreverse-phase column chromatography using 0-70% acetonitrile/H₂O as theeluent to provide the title compound (20 mg, 0.0391 mmol, 10.5% yield)as a mixture of diastereomers. MS (apci) m/z=512.3 (M+H).

Example 261

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(3-hydroxy-1-methoxy-3-methylbutan-2-yl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

Methyl2-((3R,4S)-3-(3,4-difluorophenyl)-4-(3-(2-phenyl-2,4,5,6-tetrahydro-cyclopenta[c]pyrazol-3-yl)ureido)pyrrolidin-1-yl)-3-methoxypropanoate(20 mg, 0.037 mmol, prepared as described in Example 12) was dissolvedin 1 mL of THF and cooled to 0° C. Methylmagnesium bromide (2M in THF,93 μL, 0.19 mmol) was added and the reaction was allowed to warm toambient temperature overnight. H₂O (2 mL) was added and the reaction wasextracted with DCM (2×5 mL) in a phase separator frit. The combinedorganic extracts were concentrated and purified by reverse-phase columnchromatography using 0-70% acetonitrile/H₂O as the eluent to provide thetitle compound (7.9 mg, 0.015 mmol, 39% yield) as a mixture ofdiastereomers. MS (apci) m/z=539.6 (M+H).

Example 262

2-((3R,4S)-3-(3,4-difluorophenyl)-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureido)pyrrolidin-1-yl)-3-methoxypropanoicacid hydrochloride

Methyl2-((3R,4S)-3-(3,4-difluorophenyl)-4-(3-(2-phenyl-2,4,5,6-tetrahydro-cyclopenta[c]pyrazol-3-yl)ureido)pyrrolidin-1-yl)-3-methoxypropanoate(300 mg, 0.556 mmol, prepared as described in Example 259) and NaOH (1Naqueous, 834 μL, 0.834 mmol) were combined in 1 mL of MeOH and stirredat ambient temperature overnight. The reaction was loaded onto a sampletand purified by reverse-phase column chromatography using 0-50%acetonitrile/0.01M aqueous HCl as the eluent to provide the titlecompound (298 mg, 0.530 mmol, 95.4% yield) as a mixture ofdiastereomers. MS (apci) m/z=526.2 (M+H).

Example 263

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1-hydroxy-3-methoxypropan-2-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureaStep A: Preparation of tert-butyl(3S,4R)-4-(3,4-difluorophenyl)-1-(1-hydroxy-3-methoxypropan-2-yl)pyrrolidin-3-ylcarbamate

Methyl2-((3S,4R)-3-(tert-butoxycarbonylamino)-4-(3,4-difluorophenyl)pyrrolidin-1-yl)-3-methoxypropanoate(220 mg, 0.531 mmol, prepared as described in Example 259, Step A), wasdissolved in 5 mL of THF and NaBH₄ (100 mg, 2.65 mmol) was added insmall portions. The reaction was stirred at ambient temperature for 1hour, at 40° C. for 3 h and then at 50° C. overnight. The reaction wasfiltered, concentrated, and purified by reverse-phase columnchromatography, eluting with 0-70% acetonitrile/water to afford thetitle compound (154 mg, 0.399 mmol, 75.1% yield). MS (apci) m/z=387.2(M+H).

Step B: Preparation of2-((3S,4R)-3-amino-4-(3,4-difluorophenyl)pyrrolidin-1-yl)-3-methoxypropan-1-oldihydrochloride

Tert-butyl(3S,4R)-4-(3,4-difluorophenyl)-1-(1-hydroxy-3-methoxypropan-2-yl)pyrrolidin-3-ylcarbamate(120 mg, 0.311 mmol) and HCl (5N in IPA, 186 μl, 0.932 mmol) werecombined in 5 mL of DCM and stirred at ambient temperature for 6 h. Thereaction was concentrated to afford the title compound (87 mg, 0.304mmol, 97.9% yield).

Step C: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1-hydroxy-3-methoxypropan-2-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

2-((3S,4R)-3-amino-4-(3,4-difluorophenyl)pyrrolidin-1-yl)-3-methoxypropan-1-oldihydro-chloride (13.0 mg, 0.0362 mmol), phenyl3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared accordingto the method of Example 1, Step A starting with Intermediate P135; 10.2mg, 0.0302 mmol) and DIEA (11.7 mg, 0.0905 mmol) were combined in 0.2 mLof DMF and stirred at ambient temperature for 1 hour. The reaction wasloaded onto a samplet and purified by reverse-phase columnchromatography, eluting with 0-60% acetonitrile/water, to afford thetitle compound (10.9 mg, 0.0206 mmol, 68.3% yield) MS (apci) m/z=530.2(M+H).

Example 264

1-(4-chloro-1′-methyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(1-hydroxy-3-methoxypropan-2-yl)pyrrolidin-3-yl)urea

Prepared by the method as described in Example 263, using phenyl4-chloro-1′-methyl-1-phenyl-1H, 1′H-3,4′-bipyrazol-5-ylcarbamate insteadof phenyl 3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate. Thematerial was purified by reverse-phase column chromatography using 0-80%acetonitrile/H₂O as the eluent to provide the title compound (17.2 mg,0.0293 mmol, 63.3% yield). MS (apci) m/z=586.2 (M+H).

Example 265

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-methoxy-1-phenyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)ureaStep A: Separation of racemic(trans)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-aminehydrochloride

(trans)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-aminehydrochloride (3.80 g, 11.0 mmol, prepared according to the proceduredescribed for Example 194, Step B) was separated by supercritical fluidchromatography (SFC) using a 20 mm×250 mm Chiral Tech Chiralcell OD-Hcolumn, Part #14345. The eluent was 9:1 supercritical CO₂:MeOH with 0.1%NH₄OH as a modifier. Peak 1 was isolated to provide(3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-amine (1.07 g,3.81 mmol, 34.6% yield, 98% ee). MS (apci) m/z=245.1 (M+H).

Step B: Preparation of1-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea

(3R,4S)-4-phenyl-1-(2,2,2-trifluoro-ethyl)pyrolidin-3-amine (15.0 mg,0.0614 mmol), phenyl 3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate(17.2 mg, 0.0558 mmol) and DIEA (21.6 mg, 0.167 mmol) were combined in0.2 mL of DMF and stirred at ambient temperature for 1 hour. Thereaction was loaded onto a samplet and purified by reverse-phase columnchromatography, eluting with 0-80% acetonitrile/water, to afford thetitle compound (7.2 mg, 0.0157 mmol, 28.2% yield)). (MS (apci) m/z=458.2(M+H).

Example 266

1-(3-(2-fluoroethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea

Prepared by the method as described in Example 1, Step B, using phenyl3-(2-fluoroethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate instead ofphenyl 3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate. The material waspurified by reverse-phase column chromatography using 0-80%acetonitrile/H₂O as the eluent to provide the title compound (2.2 mg,0.0044 mmol, 26% yield). MS (apci) m/z=506.2 (M+H).

Example 267

1-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea

Prepared by the method as described in Example 1, Step B, using phenyl3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (which was preparedaccording to the method of Example 1, Step A, starting with IntermediateP135) instead of phenyl 3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate.The material was purified by reverse-phase column chromatography using0-80% acetonitrile/H₂O as the eluent to provide the title compound (7.1mg, 0.0146 mmol, 42.7% yield). MS (apci) m/z=488.2 (M+H).

Example 268

1-(3-(cyanomethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea

Prepared by the method as described in Example 1, Step B, using phenyl3-(cyanomethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate instead ofphenyl 3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate. The material waspurified by reverse-phase column chromatography using 0-80%acetonitrile/H₂O as the eluent to provide the title compound (11.4 mg,0.0229 mmol, 67.0% yield). MS (apci) m/z=499.2 (M+H).

Example 269

1-(1′,4-dimethyl-1-phenyl-1H,1¹H-3,4′-bipyrazol-5-yyl)-3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea

Prepared by the method as described in Example 1, Step B, using phenyl1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-ylcarbamate instead ofphenyl 3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate. The material waspurified by reverse-phase column chromatography using 0-70%acetonitrile/H₂O as the eluent to provide the title compound (6.1 mg,0.012 mmol, 68% yield). MS (apci) m/z=524.2 (M+H).

Example 270

1-(4-chloro-1′-methyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea

Prepared by the method as described in Example 1, Step B, using phenyl4-chloro-1′-methyl-1-phenyl-1H, 1′H-3,4′-bipyrazol-5-ylcarbamate insteadof phenyl 3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate. The materialwas purified by reverse-phase column chromatography using 0-70%acetonitrile/H₂O as the eluent to provide the title compound (11.3 mg,0.0208 mmol, 60.9% yield). MS (apci) m/z=488.2 (M+H).

Example 271

1-(3-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea

Prepared by the method as described in Example 1, Step B, using(S)-phenyl3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamateinstead of phenyl 3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate. Thematerial was purified by reverse-phase column chromatography using 0-80%acetonitrile/H₂O as the eluent to provide the title compound (5.6 mg,0.00976 mmol, 28.6% yield). MS (apci) m/z=574.3 (M+H).

Example 272

1-(3-((R)-2,3-dihydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea

1-(3-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea(4.4 mg, 0.0077 mmol, prepared as described in Example 7) and HCl (7N inIPA, 3.3 μL, 0.023 mmol) were combined in 0.2 mL of IPA and stirred atambient temperature for 1 hour. The reaction was concentrated and DIEA(1.3 μL, 0.0077 mmol) was added. The crude material was purified byreverse-phase column chromatography using 0-60% acetonitrile/H₂O as theeluent to provide the title compound (3.7 mg, 0.0069 mmol, 90% yield).MS (apci) m/z=534.2 (M+H).

Example 273

(R,S)1-((2α,3β,4α)-2-methyl-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea Step A: Preparation ofN-benzyl-1-(trimethylsilyl)ethanamine

(1-chloroethyl)trimethylsilane (6.3 g, 46.1 mmol) and benzylamine (14.8g, 138 mmol) were combined in a pressure vessel and heated at 180° C.overnight. The reaction was taken up in EtOAc (200 mL), washed with 1NNaOH (100 mL), dried (MgSO₄) and concentrated. The crude product waspurified by silica gel column chromatography, eluting with 10%MeOH/CH₂Cl₂ to afford the title compound (8.10 g, 39.1 mmol, 84.7%yield). (MS (apci) m/z=208.1 (M+H).

Step B: Preparation of N-benzyl-N-(methoxymethyl)-1-(trimethyl silyl)ethanamine

A mixture of formaldehyde (37% aqueous solution, 3.45 mL, 46.3 mmol) andmethanol (1.88 mL, 46.3 mmol) at 0° C. was treated withN-benzyl-1-(trimethylsilyl)ethanamine (8.00 g, 38.6 mmol) in smallportions over 10 minutes. Additional MeOH (2 mL) was used to rinse inresidual amine. The mixture was stirred at 0° C. for 3 hours, K₂CO₃(8.00 g, 57.9 mmol) was added and the mixture was allowed to warm toambient temperature overnight. The mixture was decanted into a new flaskwith the aid of a small amount of Et₂O and additional K₂CO₃ (50 g) wasadded. The mixture was stirred for 30 minutes and filtered, washed witha small amount of Et₂O and carefully concentrated to afford the titlecompound (9.60 g, 38.2 mmol, 99.0% yield) as a pale yellow liquid. (MS(apci) m/z=208.1 (M+2H-CH₂OCH₃).

Step C: Preparation of(R,S)(2α,3β,4α)-1-benzyl-2-methyl-3-nitro-4-phenylpyrrolidine and(R,S)(3β,4α,5α)-1-benzyl-2-methyl-4-nitro-3-phenylpyrrolidine

A solution of (E)-(2-nitrovinyl)benzene (0.500 g, 3.35 mmol) and TFA(0.0258 mL, 0.335 mmol) in 10 mL of CH₂Cl₂ was cooled to 0° C. andN-benzyl-N-(methoxymethyl)-1-(trimethylsilyl)ethanamine (1.01 g, 4.02mmol) added dropwise. The reaction was stirred at 0° C. for 2 hours andthen allowed to warm to ambient temperature overnight. The reaction wasconcentrated, loaded onto a samplet using MeOH (2 mL) and DIEA (0.584mL, 3.35 mmol), and purified by reverse-phase column chromatography,eluting with 0.1% ammonium acetate buffered 5-95% acetonitrile/water, toafford the title compounds (287 mg, 0.925 mmol, 56.5% yield) as a 5:3mixture. (MS (apci) m/z=297.1 (M+H).

Step D: Preparation of(R,S)-1-((2α,3β,4α)-1-benzyl-2-methyl-4-phenyl-pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureaand(R,S)-1-((3β,4α,5α)-1-benzyl-5-methyl-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

((2α,3β,4α)-1-benzyl-2-methyl-3-nitro-4-phenylpyrrolidine and(3β,4α,5α)-1-benzyl-2-methyl-4-nitro-3-phenylpyrrolidine (110 mg of a5:3 mixture, 0.371 mmol) were dissolved in 10 mL of THF and Raney Nickel(3.18 mg, 0.0371 mmol) added. The reaction was stirred under a H₂balloon for 3 days, filtered through Celite®, concentrated, and taken upin 0.2 mL of DMF. Phenyl2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (149 mg,0.467 mmol) and DIEA (222 μL, 1.27 mmol) were added and the reaction wasstirred at ambient temperature for 1 hour. The reaction was loaded ontoa samplet and purified by reverse-phase column chromatography, elutingwith 0-80% acetonitrile/water, to afford the title compounds (172 mg,0.350 mmol, 82% yield) as a ˜7:3 mixture. (MS (apci) m/z=492.3 (M+H).

Step E: Preparation of(R,S)-1-((2α,3β,4α)-2-methyl-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureaand1-((3β,4α,5α)-5-methyl-4-phenyl-pyrro-idin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

1-((2α,3β,4α)-1-benzyl-2-methyl-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureaand1-((3β,4α,5α)-1-benzyl-5-methyl-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea(170 mg of a 7:3 mixture, 0.346 mmol) were dissolved in 10 mL of THF and10% Pd/C (36.8 mg, 0.0346 mmol) added. The reaction was stirred under aH₂ balloon for 16 hours, filtered through Celite, and concentrated toafford the title compounds (133 mg, 0.335 mmol, 96% yield) as a ˜7:3mixture. (MS (apci) m/z=402.2 (M+H).

Step F: Preparation of(R,S)-1-((2α,3β,4α)-2-methyl-4-phenyl-1-(2,2,2-trifluoro-ethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

1-((2α,3β,4α)-2-methyl-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureaand 1-((3β,4α,5α)-5-methyl-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea (20 mg of a 7:3 mixture,0.050 mmol) and DIEA (8.7 μL, 0.050 mmol) were combined in 0.2 mL of DMFand 2,2,2-trifluoroethyl trifluoromethanesulfonate (35 mg, 0.15 mmol)was added. The reaction was stirred at ambient temperature for 1 hour,loaded onto a samplet and separated by reverse-phase columnchromatography, eluting with 0-80% acetonitrile/water. Peak 1 wasisolated to afford the title compound (3.0 mg, 0.0062 mmol, 12% yield).(MS (apci) m/z=484.2 (M+H).

Example 274

(R,S)-1-((3β,4α,5α)-5-methyl-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea

Prepared by the method described in Example 9, isolating peak 2 insteadof peak 1 in Step F, to provide the title compound (1.9 mg, 0.0039 mmol,7.9% yield). MS (apci) m/z=484.2 (M+H).

Example 275

1-((3S,4R)-4-(3,4-difluorophenyl)-1-((S)-1,1,1-trifluoro-3-hydroxypropan-2-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureaStep A: Preparation of tert-butyl(3S,4R)-4-(3,4-difluorophenyl)-1-((R)-3,3,3-trifluoro-2-hydroxypropyl)pyrrolidin-3-ylcarbamate

tert-butyl (3S,4R)-4-(3,4-difluorophenyl) pyrrolidin-3-ylcarbamate (900mg, 3.017 mmol), (R)-2-(trifluoromethyl)oxirane (338.0 mg, 3.017 mmol)and DIEA (779.8 mg, 6.034 mmol) were combined in 2 mL of DMF and stirredat ambient temperature overnight. The reaction was loaded onto a sampletand purified by reverse-phase column chromatography, eluting with 0-80%acetonitrile/water, to afford the title compound (1144 mg, 2.788 mmol,92.40% yield). (MS (apci) m/z=411.2 (M+H).

Step B: Preparation of(R)-3-((3S,4R)-3-(tert-butoxycarbonylamino)-4-(3,4-difluorophenyl)pyrrolidin-1-yl)-1,1,1-trifluoropropan-2-ylmethanesulfonate

Tert-butyl(3S,4R)-4-(3,4-difluorophenyl)-1-((R)-3,3,3-trifluoro-2-hydroxypropyl)pyrrolidin-3-ylcarba-mate(900 mg, 2.19 mmol) was dissolved in 5 mL of CH₂Cl₂ and cooled to 0° C.DIEA (1146 μL, 6.58 mmol) was added followed by MsCl (204 μL, 2.63mmol). The reaction was allowed to warm to ambient temperature over 1hour, concentrated and purified by reverse-phase column chromatography,eluting with 5-90% acetonitrile/water, to afford the title compound (805mg, 1.65 mmol, 75.1% yield). (MS (apci) m/z=489.1 (M+H).

Step C: Preparation of (S)-2-((3S,4R)-3-amino-4-(3,4-difluorophenyl)pyrrolidin-1-yl)-3,3,3-trifluoropropan-1-ol

N,N,N-trimethylhexadecan-1-aminium chloride (25% solution in H₂O, 3144mg, 2.46 mmol) and(R)-3-((3S,4R)-3-(tert-butoxycarbonylamino)-4-(3,4-difluorophenyl)pyrrolidin-1-yl)-1,1,1-trifluoropropan-2-ylmethanesulfonate (800 mg, 1.64 mmol) were combined in 0.5 mL of THF andheated at 150° C. for 3 days. The reaction was loaded onto a samplet andpurified by reverse-phase column chromatography, eluting with 0-50%acetonitrile/water, to afford the title compound (287 mg, 0.925 mmol,56.5% yield). (MS (apci) m/z=311.1 (M+H).

Step D: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-((S)-1,1,1-trifluoro-3-hydroxypropan-2-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

(S)-2-((3S,4R)-3-amino-4-(3,4-difluorophenyl)pyrrolidin-1-yl)-3,3,3-trifluoro-propan-1-ol(10 mg, 0.032 mmol), phenyl3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared accordingto the method of Example 1, Step A. starting with Intermediate P135; 9.1mg, 0.027 mmol) and DIEA (10 mg, 0.081 mmol) were combined in 0.2 mL ofDMF and stirred at ambient temperature for 1 hour. The reaction wasloaded onto a samplet and purified by reverse-phase columnchromatography, eluting with 0-60% acetonitrile/water, to afford thetitle compound (8.1 mg, 0.015 mmol, 54% yield). (MS (apci) m/z=554.2(M+H).

Example 276

1-((3S,4R)-4-(3,4-difluorophenyl)-1-((S)-1,1,1-trifluoro-3-methoxypropan-2-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea StepA: Preparation of tert-butyl(3S,4R)-4-(3,4-difluorophenyl)-1-((S)-1,1,1-trifluoro-3-hydroxypropan-2-yl)pyrrolidin-3-ylcarbamate

(S)-2-((3S,4R)-3-amino-4-(3,4-difluoro-phenyl)pyrrolidin-1-yl)-3,3,3-trifluoropropan-1-ol(120 mg, 0.387 mmol, prepared as described in Example 11, Step C), Boc₂O(92.9 mg, 0.425 mmol) and PS-DMAP (27.2 mg, 0.0387 mmol) were combinedin 5 mL of CH₂Cl₂ and left to stand at ambient temperature overnight.Additional Boc₂O (30 mg, 0.14 mmol) was added followed by additionalPS-DMAP (27.2 mg, 0.0387 mmol). The reaction was left to stand for 2hours, filtered, concentrated and purified by reverse-phase columnchromatography, eluting with 5-95% acetonitrile/water, to afford thetitle compound (63 mg, 0.154 mmol, 39.7% yield). (MS (apci) m/z=411.2(M+H).

Step B: Preparation of tert-butyl(3S,4R)-4-(3,4-difluorophenyl)-1-((S)-1,1,1-trifluoro-3-methoxypropan-2-yl)pyrrolidin-3-ylcarbamate

Tert-butyl(3S,4R)-4-(3,4-difluorophenyl)-1-((S)-1,1,1-trifluoro-3-hydroxypropan-2-yl)pyrrolidin-3-ylcarbamate(25 mg, 0.061 mmol) and Ag₂O (28 mg, 0.12 mmol) ware combined in 1 mL oftoluene and stirred at 0° C. Iodomethane (10 mg, 0.073 mmol) was addedand the reaction was allowed to warm to ambient temperature and stirredfor 5 hours. Acetonitrile (0.5 mL) and additional iodomethane (10 mg,0.073 mmol) were added and the reaction was stirred at ambienttemperature overnight, filtered through Celite®, concentrated andpurified by purified by reverse-phase column chromatography, elutingwith 5-95% acetonitrile/water, to afford the title compound (22 mg,0.052 mmol, 85% yield). (MS (apci) m/z=425.2 (M+H).

Step C: Preparation of(3S,4R)-4-(3,4-difluorophenyl)-1-((S)-1,1,1-trifluoro-3-methoxypropan-2-yl)pyrrolidin-3-aminedihydrochloride

Tert-butyl(3S,4R)-4-(3,4-difluorophenyl)-1-((S)-1,1,1-trifluoro-3-methoxypropan-2-yl)pyrrolidin-3-ylcarbamate(20 mg, 0.0471 mmol) and HCl (5N in IPA, 37.7 μL, 0.188 mmol) werecombined in 5 mL of CH₂Cl₂ and stirred at ambient temperature for 6hours. The reaction was concentrated to afford the title compound (15mg, 0.0463 mmol, 98.2% yield). (MS (apci) m/z=325.1 (M+H).

Step D: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-((S)-1,1,1-trifluoro-3-methoxypropan-2-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

(3S,4R)-4-(3,4-difluorophenyl)-1-((S)-1,1,1-trifluoro-3-methoxypropan-2-yl)pyrrolidin-3-aminedihydrochloride (7.5 mg. 0.019 mmol), phenyl3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared accordingto the method of Example 1, Step A, starting with Intermediate P135; 5.8mg, 0.017 mmol) and DIEA (6.7 mg, 0.051 mmol) were combined in 0.2 mL ofDMF and stirred at ambient temperature for 1 hour. The reaction wasloaded onto a samplet and purified by reverse-phase columnchromatography, eluting with 0-90% acetonitrile/water, to afford thetitle compound (6.8 mg, 0.012 mmol, 70% yield). (MS (apci) m/z=568.2(M+H).

Example 277

1-((3S,4R)-4-(3,4-difluorophenyl)-1-((S)-1,1,1-trifluoro-3-methoxypropan-2-yl)pyrrolidin-3-yl)-3-(3-((S)-2-hydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared by the method as described in Example 12, Step D using(S)-phenyl3-(2-hydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate insteadof phenyl 3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate. Thematerial was purified by reverse-phase column chromatography using 0-70%acetonitrile/H₂O as the eluent to provide the title compound (7.7 mg,0.013 mmol, 75% yield). MS (apci) m/z=598.3 (M+H).

Example 278

1-(4-chloro-1′-methyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-((R)-1,1,1-trifluoro-3-methoxypropan-2-yl)pyrrolidin-3-yl)ureaStep A: Preparation of(S)-3-((3S,4R)-3-(tert-butoxycarbonylamino)-4-(3,4-difluorophenyl)pyrrolidin-1-yl)-1,1,1-trifluoropropan-2-ylmethanesulfonate

(tert-butyl (3S,4R)-4-(3,4-difluorophenyl)pyrrolidin-3-ylcarbamate (1000mg, 3.352 mmol), (S)-2-(trifluoromethyl)oxirane (413.2 mg, 3.687 mmol)and DIEA (866.4 mg, 6.704 mmol) were combined in 2 mL of DMF and stirredat ambient temperature overnight. Methanesulfonyl chloride (285.4 μL,3.687 mmol) was added and the reaction was stirred for 1 hour.Additional methanesulfonyl chloride (285.4 μL, 3.687 mmol) was added twomore times with stirring for 20 minutes each. The reaction was loadedonto a samplet and purified by reverse-phase column chromatography,eluting with 0-80% acetonitrile/water, to afford the title compound(1194 mg, 2.444 mmol, 72.92% yield). (MS (apci) m/z=411.1 (M+H).

Step B: Preparation of(3S,4R)-4-(3,4-difluorophenyl)-1-((R)-1,1,1-trifluoro-3-methoxypropan-2-yl)pyrrolidin-3-amine

N,N,N-trimethylhexadecan-1-aminium hydrogen-sulfate (281 mg, 0.737 mmol)and(S)-3-((3S,4R)-3-(tert-butoxycarbonylamino)-4-(3,4-difluorophenyl)pyrrolidin-1-yl)-1,1,1-trifluoropropan-2-ylmethanesulfonate (180 mg, 0.368 mmol) were combined in 10 mL of MeOH ina pressure vessel and heated 170° C. for 20 hours. The reaction wasloaded onto a samplet and purified by reverse-phase columnchromatography, eluting with 0-95% acetonitrile/water, to afford thetitle compound (67 mg, 0.207 mmol, 56.1% yield). (MS (apci) m/z=425.1(M+H).

Step C: 1-(4-chloro-1′-methyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-((R)-1,1,1-trifluoro-3-methoxypropan-2-yl)pyrrolidin-3-yl)urea

Phenyl 4-chloro-1′-methyl-1-phenyl-1H, 1′H-3,4′-bipyrazol-5-ylcarbamate(25 mg, 0.0635 mmol),(3S,4R)-4-(3,4-difluorophenyl)-1-((R)-1,1,1-trifluoro-3-methoxypropan-2-yl)pyrrolidin-3-aminedihydrochloride (27.7 mg, 0.069 mmol) and DIEA (24.6 mg, 0.190 mmol)were combined in 0.2 mL of DMF and stirred at ambient temperature for 1hour. The reaction was loaded onto a samplet and purified byreverse-phase column chromatography, eluting with 0-80%acetonitrile/water, to afford the title compound (17.2 mg, 0.0276 mmol,43.4% yield). (MS (apci) m/z=624.2 (M+H).

Example 279

1-((3S,4R)-4-(3,4-difluorophenyl)-1-((R)-1,1,1-trifluoro-3-methoxypropan-2-yl)pyrrolidin-3-yl)-3-(3-((S)-2-hydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared by the method as described in Example 14, Step C using(S)-phenyl3-(2-hydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate insteadof phenyl 4-chloro-1′-methyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-ylcarbamate. The material was purified byreverse-phase column chromatography using 0-75% acetonitrile/H₂O as theeluent to provide the title compound (13.0 mg, 0.0218 mmol, 95.1%yield). MS (apci) m/z=598.3 (M+H).

The following compound was prepared according to the method of Example52 using the appropriate starting materials.

Ex # Structure Name 280

1-((3S,4R)-4-(3,4- difluorophenyl)-1- (2-methoxyethyl)pyrrolidin-3-yl)-3- (3-methyl-4- (methylthio)-1- phenyl-1H-pyrazol-5-yl)urea MS (apci) m/z = 518.2 (M + H).

The following compounds were prepared according to the method of Example1, Step B, using the appropriate starting materials.

MS (apci) Ex. # Structure Name m/z 281

1-((3S,4R)-4-(3,5- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-methoxypropyl)-4- methyl-1-phenyl-1H-pyrazol- 5-yl)urea 528.3(M + H) 282

1-(3-(1,1-difluoro-2- hydroxyethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3- ((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 536.3 (M + H) 283

1-(3-(1,1-difluoro-2- hydroxyethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3- ((3S,4R)-4-(3,5- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 536.2 (M + H) 284

1-(3-(1,1-difluoro-2- hydroxyethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3- ((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 518.2 (M + H) 285

1-(3-(1,1-difluoro-2- hydroxyethyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4- (3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 522.2 (M + H) 286

1-((3S,4R)-4-(3,5- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-hydroxyethyl)-4- methyl-1-phenyl-1H-pyrazol- 5-yl)urea 500.3(M + H) 287

1-((3S,4R)-4-(4-fluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-hydroxyethyl)-4- methyl-1-phenyl-1H-pyrazol- 5-yl)urea482.3 (M + H) 288

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-hydroxy-2- methylpropyl)-4-methyl-1- phenyl-1H-pyrazol-5-yl)urea528.3 (M + H) 289

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-((S)-2-hydroxypropyl)-4- methyl-1-phenyl-1H-pyrazol- 5-yl)urea514.3 (M + H) 290

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-(R)-2-hydroxypropyl)-4- methyl-1-phenyl-1H-pyrazol- 5-yl)urea 514.3(M + H) 291

ethyl 5-(3-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)ureido)-4-methyl-1-phenyl-1H-pyrazole-3-carboxylate 528.3 (M + H) 292

5-(3-((3S,4R)-4-(4- fluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)ureido)-N,4-dimethyl-1- phenyl-1H-pyrazole-3- carboxamide 495.2 (M +H) 293

1-(trans-4-(3-chloro-4- fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)- 3-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5- yl)urea 552.2 (M + H) 294

1-(trans-4-(4-chloro-3- fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)- 3-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5- yl)urea 552.2 (M + H) 295

1-(trans-4-(3-chloro-5- fluorohenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)- 3-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5- yl)urea 552.2 (M + H) 296

1-(trans-4-(3-chlorophenyl)-1- (2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl- 1H,1′H-[3,4′-bipyrazol]-5- yl)urea 534.2(M + H) 297

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(5-methyl-1,3,4- oxadiazol-2-yl)-1-phenyl-1H-pyrazol-5-yl)urea 538.2 (M + H) 298

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(3-methyl-1,2,4- oxadiazol-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea 538.2 (M + H) 299

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(3- (trifluoromethyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-5- yl)urea 592.2 (M + H) 300

1-((3S,4R)-4-(4-fluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3- (3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-5- yl)urea 574.2 (M + H) 301

5-(3-(trans-4-(3-chloro-4- fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)ureido)-N,4-dimethyl-1-phenyl-1H-pyrazole-3- carboxamide 529.2 (M + H) 302

5-(3-(trans-4-(4-chloro-3- fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)ureido)-N,4-dimethyl-1-phenyl-1H-pyrazole-3- carboxamide 529.2 (M + H) 303

1-(trans-4-(4-chloro-3- fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)- 3-(4-methyl-3-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)- 1-phenyl-1H-pyrazol-5-yl)urea 579.2 (M +H) 304

1-(trans-4-(3-chloro-4- fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)- 3-94-methyl-3-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)- 1-phenyl-1H-pyrazol-5-yl)urea 579.2 (M +H) 305

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(1′,4,5′-trimethyl-1-phenyl- 1H,1′H-[3,3′-bipyrazol]-5- yl)urea 550.2(M + H) 306

1-((3S,4R)-4-(3,5- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(1′,4,5′-trimethyl-1-phenyl- 1H,1′H-[3,3′-bipyrazol]-5- yl)urea 550.2(M + H) 307

1-((3S,4R)-4-(4-fluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4,5′-trimethyl-1- phenyl-1H,1′H-[3,3′- bipyrazol]-5-yl)urea532.3 (M + H) 308

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(2′,4,5′-trimethyl-1-phenyl- 1H,2′H-[3,3′-bipyrazol]-5- yl)urea 550.2(M + H) 309

1-(4-cyclopropyl-1′-methyl-1- phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4- (3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 562.2 (M + H) 310

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(4-isopropyl-1′-methyl-1- phenyl-1H,1′H-[3,4′- bipyrazol]-5-yl)urea564.3 (M + H) 311

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(4-ethyl-1′-methyl-1-phenyl- 1H,1′H-[3,4′-bipyrazol]-5- yl)urea 550.2(M + H) 312

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(1-(4-fluorophenyl)-1′,4- dimethyl-1H,1′H-[3,4′- bipyrazol]-5-yl)urea554.2 (M + H) 313

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(1-(3-fluorophenyl)-1′,4- dimethyl-1H,1′H-[3,4′- bipyrazol]-5-yl)urea554.2 (M + H) 314

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(1-(2-fluorophenyl)-1′,4- dimethyl-1H,1′H-[3,4′- bipyrazol]-5-yl)urea554.2 (M + H) 315

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(1-(3-chlorophenyl)-1′,4- dimethyl-1H,1′H-[3,4′- bipyrazol]-5-yl)urea571.2 (M + H) 316

1-(1-(3-chloro-4- fluorophenyl)-1′,4-dimethyl-1H,1′H-[3,4′-bipyrazol]-5-yl)- 3-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 589.2 (M + H) 317

1-(1-(3-chloro-2- fluorophenyl)-1′,4-dimethyl-1H,1′H-[3,4′-bipyrazol]-5-yl)- 3-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 589.2 (M + H) 318

1-((3S,4R)-4-(4-fluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-(4-fluorophenyl)- 1′,4-dimethyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea 568.2 (M + H) 319

1-((3S,4R)-4-(4-fluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-(3-fluorophenyl)- 1′,4-dimethyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea 568.2 (M + H) 320

1-((3S,4R)-4-(4-fluorophenyl)- 3-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-(2-fluorophenyl)- 1′,4-dimethyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea 568.2 (M + H) 321

1-((3S,4R)-4-(3,4- fluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(1-(3-chlorophenyl)-1′,4- dimethyl-1H,1′H-[3,4′- bipyrazol]-5-yl)urea550.2 (M + H) 322

1-(1-(3-chloro-4- fluorophenyl)-1′,4-dimethyl-1H,1′H-[3,4′-bipyrazol]-5-yl)- 3-((3S,4R)-4-(4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 568.2 (M− H). 323

1-(1-(3-chloro-2- fluorophenyl)-1′,4-dimethyl-1H,1′H-[3,4′-bipyrazol-5-yl)- 3-((3S,4R)-4-(4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 568.2 (M− H). 324

1-((3S,4R)-4-(2,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl- 1H,1′H-[3,4′-bipyrazol]-5- yl)urea 536.2 (M +H) 325

1-((3S,4R)-4-(3-cyanophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1- phenyl-1H,1′H-[3,4′- bipyrazol]-5-yl)urea523.2 (M + H) 326

1-((3S,4R)-4-(4-cyanophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1- phenyl-1H,1′H-[3,4′- bipyrazol]-5-yl)urea523.2 (M + H) 327

1-(1′,4-dimethyl-1-phenyl- 1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-1-(2- methoxyethyl)-4-(p- tolyl)pyrrolidin-3-yl)urea 514.3(M + H) 328

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1,3-diphenyl-1H- pyrazol-5-yl)urea 532.2 (M + H) 329

1-((3S,4R)-4-(3,5- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1,3-diphenyl-1H- pyrazol-5-yl)urea 532.2 (M + H) 330

1-((3S,4R)-4-(3,4,5- trifluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)- 3-(4-methyl-1,3-diphenyl-1H-pyrazol-5-yl)urea 550.2 (M + H) 331

1-((3S,4R)-4-(4- fluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1,3-diphenyl-1H- pyrazol-5-yl)urea 514.3 (M + H) 332

1-(4-bromo-3-methyl-1- phenyl-1H-pyrazol-5-yl)-3-trans-1-(2-methoxyethyl)-4-(1- methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)urea 502.1 (M + H) 333

1-(1′,4-dimethyl-1-phenyl- 1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(trans-1-(2-methoxyethyl)-4- (1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)urea 519.2 (M + H) 334

1-(1′,4-dimethyl-1-phenyl- 1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((trans-1-(2-methoxyethyl)- 4-(1,2,3-thiadiazol-4-yl)pyrrolidin-3-yl)urea 507.6 (M + H) 335

1-(3-ethoxy-4-methyl-1- phenyl-1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4- (3- (trifluoromethyl)phenyl)pyrrolidin-3-yl)urea 532.3 (M + H) 336

1-(3,4-dimethyl-1-phenyl-1H- pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-(3- (trifluoromethyl)phenyl)pyrrolidin- 3-yl)urea 502.2(M + H) 337

1-((3S,4R)-4-(5-fluoropyridin- 3-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)- 3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol- 3-yl)urea 465.2 (M + H) 338

1-((3R,4S)-4-(5-fluoropyridin- 3-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)- 3-92-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol- 3-yl)urea 465.2 (M + H) 339

1-(3-(2-fluoroethoxy)-4- methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(5- fluoropyridin-3-yl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 501.2 (M + H) 340

1-(3-(2-fluoroethoxy)-4- methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-(5- fluoropyridin-3-yl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 501.2 (M + H) 341

1-(trans-4-(5-fluoropyridin-3- yl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6- tetrahydrocyclopenta[c]pyrazol- 3-yl)urea 465.2(M + H) 342

1-(trans-4-(5-chloropyridin-3- yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-ethoxy-4- methyl-1-phenyl-1H-pyrazol- 5-yl)urea500.2 (M + H) 343

1-(trans-4-(5-chloropyridin-3- yl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-93,4-dimethyl-1-phenyl-1H- pyrazol-5-yl)urea 469.2 (M + H) 344

1-(trans-4-(5-fluoropyridin-3- yl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1,3-diphenyl-1H- pyrazol-5-yl)urea 515.3 (M + H) 345

1-(1′,4-dimethyl-1-phenyl- 1H,1′H-[3,4′-bipyrazol]-5-yl)-3-(trans-4-(5-fluoropyridin-2- yl)-1-(2- methoxyethyl)pyrrolidin-3-yl)urea 515.3 (M + H) 346

1-(1′,4-dimethyl-1-phenyl- 1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4-(3-fluoropyridin- 4-yl)-1-(2- methoxyethyl)pyrrolidin-3-yl)urea 519.2 (M + H) 347

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(1-methyl-1H- 1,2,4-triazol-3-yl)-1-phenyl-1H-pyrazol-5-yl)urea 537.2 (M + H) 348

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(1′-(2-methoxyethyl)-4- methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea 580.3 (M + H) 349

1-(3-cyano-4-methyl-1- phenyl-1H-pyrazol-5-yl)-3- ((3S,4R)-4-(3,4-difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3- yl)urea 480.8 (M + H)350

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(1′-(2-hydroxyethyl)-4- methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea 565.8 (M + H) 351

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methyl-2H- 1,2,3-triazol-4-yl)-1-phenyl-1H-pyrazol-5-yl)urea 536.8 (M + H) 352

1-(3-bromo-4-methyl-1- phenyl-1H-pyrazol-5-yl)-3- ((3S,4R)-4-(3,4-difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3- yl)urea 533.7 (M + H)353

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(5-methyl-6-oxo-2-phenyl- 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)urea 510.8 (M + H) 354

1-((3S,4R)-4-(3,5- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(5-methyl-6-oxo-2-phenyl- 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)urea 510.8 (M + H) 355

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-((5-methyl- 1,3,4-oxadiazol-2- yl)methoxy)-1-phenyl-1H-pyrazol-5-yl)urea 568.3 (M + H) 356

1-(4-chloro-3-ethoxy-1- phenyl-1H-pyrazol-5-yl)-3- ((3S,4R)-4-(3,4-difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3- yl)urea 520.2 (M + H)357

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-fluoro-1- phenyl-1H-pyrazol-5-yl)urea 504.2 (M + H) 358

1-(4-bromo-3-(2-hydroxy-2- methylpropoxy)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4- (3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 608.2 (M + H) 359

1-(4-chloro-3-(2-hydroxy-2- methylpropoxy)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4- (3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl(urea 564.2 (M + H) 360

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-((S)-2-hydroxybutoxy)-4- methyl-1-phenyl-1H-pyrazol- 5-yl)urea544.3 (M + H) 361

ethyl 2-((5-(3-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yl)oxy)acetate 558.3 (M + H) 362

1-((3S,4R)-4-(4-fluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-hydroxy-2- methylpropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea 526.3 (M + H) 363

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-hydroxy-2- methylpropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea 544.3 (M + H) 364

1-((3S,4R)-4-(4-fluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((R)-2- hydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea 512.3 (M + H) 365

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-((R)-2-hydroxypropoxy)- 4-methyl-1-phenyl-1H- pyrazol-5-yl)urea530.3 (M + H) 366

1-((3S,4R)-4-(3,5- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-((R)-2-hydroxypropoxy)- 4-methyl-1-phenyl-1H- pyrazol-5-yl)urea530.3 (M + H) 367

1-((3S,4R)-4-(3,5- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-((R)- 3,3,3-trifluoro-2-hydroxypropoxy)-1H-pyrazol- 5-yl)urea 584.2 (M + H) 368

1-((3S,4R)-4-(4-fluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((S)-2- hydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea 512.3 (M + H) 369

1-((3S,4R)-4-(3,5- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-((S)- 3,3,3-trifluoro-2-hydroxypropoxy)-1H-pyrazol- 5-yl)urea 584.3 (M + H) 370

1-(4-chloro-3-(2-hydroxy-2- methylpropoxy)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4- (3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 564.2 (M + H) 371

1-(4-chloro-3-(2-hydroxy-2- methylpropoxy)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(4- fluorophenyl)-1-(2-methoxyetyl)pyrrolidin-3- yl)urea 546.2 (M + H) 372

1-(4-chloro-3-((R)-2- hydroxypropoxy)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4- (3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 550.2 (M + H) 373

1-(4-chloro-3-((R)-2- hydroxypropoxy)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4- (3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 550.2 (M + H) 374

1-(4-chloro-3-((R)-2- hydroxypropoxy)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4- (4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 532.2 (M + H) 375

1-(4-bromo-3-((R)-2- hydroxypropoxy)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4- (3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 594.2 (M + H) 376

1-(4-bromo-3-((R)-2- hydroxypropoxy)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4- (3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 594.2 (M + H) 377

1-(4-bromo-3-((R)-2- hydroxypropoxy)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4- (4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 576.2 (M + H) 378

1-((3S,4R)-4-(3,5- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-((R)-2-hydroxybutoxy)-4- methyl-1-phenyl-1H-pyrazol- 5-yl)urea544.3 (M + H) 379

1-((3S,4R)-4-(4-fluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((R)-2- hydroxybutoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea 526.3 (M + H) 380

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-((R)-2-hydroxybutoxy)-4- methyl-1-phenyl-1H-pyrazol- 5-yl)urea544.3 (M + H) 381

ethyl 4-bromo-5-(3-((3S,4R)- 4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)ureido)-1-phenyl-1H-pyrazole-3-carboxylate 592.2 (M + H) 382

1-((3S,4R)-4-(4-fluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′-(2-methoxyethyl)- 4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea 562.3 (M + H) 383

1-((3S,4R)-4-(3-fluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′-(2-methoxyethyl)- 4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea 562.3 (M + H) 384

1-((3S,4R)-4-(3-fluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methyl- 3H-1,2,3-triazol-4-yl)-1-phenyl-1H-pyrazol-5-yl)urea 519.3 (M + H) 385

1-((3S,4R)-4-(4-fluorophenyl)- 1-92-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methyl- 2H-1,2,3-triazol-4-yl)-1-phenyl-1H-pyrazol-5-yl)urea 519.3 (M + H) 386

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2- morpholinoethoxy)-1-phenyl- 1H-pyrazol-5-yl)urea 585.3(M + H) 387

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-(1,3-dioxoisoindolin-2- yl)ethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea 645.3 (M + H) 388

tert-butyl 4-(2-((5-(3-((3S,4R)- 4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)ureido)-4-methyl-1-phenyl- 1H-pyrazol-3-yl)oxy)ethyl)piperazine-1- carboxylate 684.4 (M + H) 389

Trans-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)-3-(2-phenyl-2H-indazol-3-yl)urea 456.2 (M + H) 390

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2H-indazol-3- yl)urea 492.0 (M + H) 391

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-94-methyl-3-((1-methyl-1H- 1,2,4-triazol-3-yl)methoxy)-1-phenyl-1H-pyrazol-5-yl)urea 567.3 (M + H) 392

1-((3S,4R)-4-(3,5- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-(((R)-2,2-dimethyl-1,3- dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol- 5-yl)urea 586.2 (M + H) 393

1-((3S,4R)-4-(3,5- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-(((S)-2,2-dimethyl-1,3- dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol- 5-yl)rea 586.2 (M + H) 394

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1- (pyrazin-2-yl)-1H-pyrazol-5- yl)urea 502.2 (M +H) 395

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(2-pyridazin-4-yl)-2,4,5,6- tetrahydrocyclopenta[c]pyrazol- 3-yl)urea484.2 (M + H) 396

5-(3-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl- 1H-pyrazol-3-yl dimethylcarbamate 543.2(M + H) 397

5-(3-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl- 1H-pyrazol-3-yl morpholine-4- carboxylate585.3 (M + H) 398

1-(3-(((S)-2,2-dimethyl-1,3- dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol- 5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5- trifluorophenyl)pyrrolidin-3- yl)urea 604.3 (M +H) 399

1-(3-(((R)-2,2-dimethyl-1,3- dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol- 5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5- trifluorophenyl)pyrrolidin-3- yl)urea 604.3 (M +H) 400

1-(3-((S)-2-(tert- butyldimethylsilyloxy)propoxy)- 4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2- methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3- yl)urea 662.3 (M + H) 401

1-(3-(2-hydroxy-2- methylpropoxy)-4-methyl-1- phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)- 4-(3,4,5- trifluorophenyl)pyrrolidin-3-yl)urea 562.3 (M + H) 402

1-(3-((S)-2-(tert- butyldimethylsilyloxy)-3- methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3- ((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 674.3 (M + H)

The following compounds were prepared according to the method of Example1, Step B, using the appropriate halogenated pyrazole carbamate startingmaterials.

MS (apci) Ex. # Structure Name m/z 403

1-(4-chloro-3-(methoxy- methyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 520.2 (M + H) 404

1-(4-bromo-3-(methoxy- methyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 564.1 (M + H) 405

1-(4-chloro-3-(methoxy- methyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,5- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 520.2 (M + H) 406

1-(4-bromo-3-(methoxy- methyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,5- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 564.1 (M + H) 407

1-(4-chloro-3-(methoxy- methyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(4- fluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)urea 502.2 (M + H) 408

1-(4-bromo-3-(methoxy- methyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(4- fluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)urea 546.2 (M + H) 409

1-(4-chloro-3-(1,1-difluoro-2- hydroxyethyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4- (3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 556.2 (M + H) 410

1-(4-chloro-3-(1,1-difluoro-2- hydroxyethyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4- (3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 556.2 (M + H) 411

1-(4-chloro-3-(1,1-difluoro-2- hydroxyethyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(4- fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 538.2 (M + H) 412

1-(4-chloro-3-((S)-2- hydroxypropyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4- (3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 534.2 (M + H) 413

1-(4-chloro-3-((R)-2- hydroxypropyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4- (3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 534.2 (M + H) 414

1-(4-bromo-3-((R)-2- hydroxypropyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4- (3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 578.2 (M + H) 415

1-(4-chloro-3-(2-hydroxy-2- methylpropyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4- (3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 548.2 (M + H) 416

1-(4-chloro-3-(3-methyl-1,2,4- oxadiazol-5-yl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4- (3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 558.1 (M + H) 417

1-(4-bromo-3-(2-cyanopropan- 2-yl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)urea 587.2 (M + H) 418

1-(4-chloro-3-(2-cyanopropan- 2-yl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)urea 543.2 (M + H) 419

1-(4-bromo-1′-methyl-1- phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4- (3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 602.2 (M + H) 420

1-(4-bromo-1′-methyl-1- phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4- (3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 602.2 (M + H) 421

1-(4-bromo-1′-methyl-1- phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4- (4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 582.2 (M + H) 422

1-(4-chloro-1′-methyl-1- phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4- (3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 556.2 (M + H) 423

1-(4-chloro-1′-methyl-1- phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4- (3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 556.2 (M + H) 424

1-(4-chloro-1′-methyl-1- phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4- (4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 538.2 (M + H) 425

1-(4-chloro-1′-methyl-1- phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4- phenyl-1-(2- methoxyethyl)pyrrolidin-3-yl)urea 520.0 (M + H) 426

1-(4-chloro-1,3-diphenyl-1H- pyrazol-5-yl)-3-((3S,4R)-4-(3,5-difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3- yl)urea 552.2 (M +H) 427

1-(4-bromo-1,3-diphenyl-1H- pyrazol-5-yl)-3-((3S,4R)-4-(3,5-difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3- yl)urea 598.2 (M +H) 428

1-(4-bromo-1,3-diphenyl-1H- pyrazol-5-yl)-3-((3S,4R)-4-(4-fluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3- yl)urea 578.4 (M + H) 429

1-(4-chloro-3-methyl-1- phenyl-1H-pyrazol-5-yl)-3- ((3S,4R)-4-(3,5-difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3- yl)urea 554.2 (M + H)430

1-(4-bromo-3-methyl-1- phenyl-1H-pyrazol-5-yl)-3- ((3S,4R)-4-(3,5-difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3- yl)urea 501.1 (M + H)431

1-(4-chloro-1′-methyl-1- phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4- (5-fluoropyridin-3-yl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 540.2 (M + H) 432

1-(4-fluoro-1′-methyl-1- phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4- (5-fluoropyridin-3-yl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 523.2 (M + H) 433

1-(4-bromo-3-methyl-1- phenyl-1H-pyrazol-5-yl)-3-trans-4-(5-fluoropyridin-3-yl)- 1-(2-methoxyethyl)pyrrolidin- 3-yl)urea519.1 (M + H) 434

1-(4-bromo-3-methyl-1- phenyl-1H-pyrazol-5-yl)-3-trans-4-(5-fluoropyridin-3-yl)- 1-(2-methoxyethyl)pyrrolidin- 3-yl)urea473.2 (M + H) 435

1-(4-bromo-1,3-diphenyl-1H- pyrazol-5-yl)-3-(trans-4-(5-fluoropyridin-3-yl)-1-(2- methoxyethyl)pyrrolidin-3- yl)urea 579.2 (M +H) 436

1-(4-chloro-1,3-diphenyl-1H- pyrazol-5-yl)-3-(trans-4-(5-fluoropyridin-3-yl)-1-(2- methoxyethyl)pyrrolidin-3- yl)urea 535.2 (M +H) 437

1-(4-bromo-3-methyl-1- phenyl-1H-pyrazol-5-yl)-3-(trans-4-(5-fluoropyridin-2- yl)-1-(2- methoxyethyl)pyrrolidin-3-yl)urea 525.2 (M + H) 438

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(4-fluoro-1′-methyl-1- phenyl-1H,1′H-[3,4′- bipyrazol]-5-yl)urea 540.2(M + H) 439

1-((3S,4R)-4-(3,5- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(4-fluoro-1′-methyl-1- phenyl-1H,1′H-[3,4′- bipyrazol]-5-yl)urea 540.2(M + H) 440

1-(4-bromo-1′-methyl-1- phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4- (5-fluoropyridin-3-yl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 585.2 (M + H)

Example 441

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

To a suspension of(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride (Preparation L1; 40 mg, 0.13 mmol) in DMA (428 μL) wasadded DIEA (112 μL, 0.64 mmol) to obtain a clear solution. To thissolution was added phenyl1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-ylcarbamate (Intermediate199; 53 mg, 0.14 mmol). After overnight stirring, the reaction wasdirectly purified by reverse-phase chromatography (C18, 5 to 42%acetonitrile/water) to yield the 1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureaas white solid (42 mg, 63%). MS (apci) m/z=518.3 (M+H). ¹H NMR (400 MHz,CDCl₃) δ 7.85 (s, 1H), 7.74 (s, 1H), 7.48-7.5 (m, 2H), 7.34-7.38 (m,2H), 7.27-7.31 (m, 1H), 7.05-7.1 (m, 2H), 6.81-6.85 (m, 2H), 5.37 (br s,1H), 4.27 (br s, 1H), 3.96 (s, 3H), 3.33-3.43 (m, 2H), 3.25 (br s, 3H),3.16-3.19 (m, 1H), 2.98 (br s, 1H), 2.70-2.83 (m, 2H), 2.49-2.65 (m,2H), 2.27 (t, 1H), 2.09 (s, 3H).

Example 442

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the method described in for Example 441, replacing(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride with(3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride in Step F. MS (apci) m/z=536.3 (M+H). ¹H NMR (400 MHz,CDCl₃) δ 7.86 (s, 1H), 7.74 (s, 1H), 7.49-7.52 (m, 2H), 7.36-7.41 (m,2H), 7.28-7.33 (m, 1H), 6.62-6.70 (m, 3H), 5.33 (br s, 1H), 4.27 (br s,1H), 3.96 (s, 3H), 3.36-3.45 (m, 2H), 3.27 (br s, 3H), 3.15-3.20 (m,1H), 2.96 (br s, 1H), 2.72-2.81 (m, 2H), 2.54-2.67 (m, 2H), 2.31 (t,1H), 2.11 (s, 3H).

Example 443

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4-(3,4,5-trifluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the method described in for Example 441, replacing(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride with(3S,4R)-4-(3,4,5-trifluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride in Step F. MS (apci) m/z=554.3 (M+H).

Example 444

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the method described in Example 441, replacing(3S,4R)-4-(2,4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride with(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride and in Step F. MS (apci) m/z=554.3 (M+H). ¹H NMR (400MHz, CDCl₃) δ 7.86 (s, 1H), 7.74 (s, 1H), 7.48-7.52 (m, 2H), 7.34-7.39(m, 2H), 7.28-7.32 (m, 1H), 6.92-7.04 (m, 2H), 6.81-6.85 (m, 1H), 5.32(br s, 1H), 4.24 (br s, 1H), 3.96 (s, 3H), 3.38-3.40 (m, 2H), 3.26 (brs, 3H), 3.12-3.17 (m, 1H), 2.91 (br s, 1H), 2.72-2.77 (m, 2H), 2.52-2.66(m, 2H), 2.27 (t, 1H), 2.1 (s, 3H).

Example 445

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4-(fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the method described in Example 441, replacing(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride with(3S,4R)-4-(phenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloridein Step F. MS (apci) m/z=500.3 (M+H).

Example 446

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′-(4-methoxybenzyl)-4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea

Prepared according to the method described in Example 441, replacing(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride with(3S,4R)-4-(3,4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride and phenyl 1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-ylcarbamate with phenyl(1′-(4-methoxybenzyl)-4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)carbamatein Step F. MS (apci) m/z=642.3 (M+H).

Example 447

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′-(4-methoxybenzyl)-4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea trifluoroacetate

A mixture of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′-(4-methoxybenzyl)-4-methyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)urea(300 mg, 0.468 mmol) and TFA (720 μL, 9.35 mmol) in a pressure vesselwas sealed and heated at 60° C. The reaction was heated for 18 hours,then cooled and ether (30 mL) was added and the resulting mixture wassonicated to provide the crude product as a beige solid. The solid wasdissolved in minimal amount of MeOH and purified by reverse-phasechromatography (C18, 5 to 35% to 50% acetonitrile/water) to provide1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′-(4-methoxybenzyl)-4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea as the triflate salt (135 mg. 38%).

Example 448

2-(4-chloro-5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazol-3-yl)ethylacetate Step A: Preparation of2-(4-chloro-5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yl)ethylacetate and phenyl(3-(2-((phenoxycarbonyl)oxy)ethyl)-1-phenyl-1H-pyrazol-5-yl)carbamate

To a solution of 2-(5-amino-1-phenyl-1H-pyrazol-3-yl)ethanol(Intermediate 161, 242 mg, 1.191 mmol) in EtOAc (10 mL) was addedaqueous sodium hydroxide (2M, 1.19 mL, 2.38 mmol) then phenylcarbonochloridate (0.179 mL, 1.43 mmol). The reaction was stirred atambient temperature for 4 hours and then the phases were separated. Theorganic phase was washed with H₂O (5 mL), brine (5 mL), dried withMgSO₄, filtered and concentrated to afford the product as a tan solid(250 mg), a mixture of two components:2-(4-chloro-5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yl)ethylacetate and phenyl(3-(2-((phenoxycarbonyl)oxy)ethyl)-1-phenyl-1H-pyrazol-5-yl)carbamatewhich were used without purification in the next step.

Step B: Preparation of2-(4-chloro-5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yl)ethylacetate and phenyl(4-chloro-3-(2-((phenoxycarbonyl)oxy)ethyl)-1-phenyl-1H-pyrazol-5-yl)carbamate

To a solution of2-(4-chloro-5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yl)ethylacetate and phenyl(3-(2-((phenoxycarbonyl)oxy)ethyl)-1-phenyl-1H-pyrazol-5-yl)carbamate(250 mg, 0.773 mmol) in DCM (10 mL) were added pyridinium4-methylbenzenesulfonate (PPTS) (19.4 mg, 0.077 mmol) andn-chlorosuccinimide (155 mg, 1.16 mmol). The reaction was stirred atambient temperature for 4 days, then diluted with H₂O (10 mL), phasesseparated and aqueous phase extracted DCM (2×20 mL). The combinedorganic phases were dried (MgSO₄), filtered and concentrated. The crudeoil was purified by silica column chromatography eluting with 40%acetone/hexanes to afford a the product as an orange oil (63 mg), amixture of two components:2-(4-chloro-5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yl)ethylacetate, MS (apci) m/z=400.1 (M+H), and phenyl(4-chloro-3-(2-((phenoxycarbonyl)oxy)ethyl)-1-phenyl-1H-pyrazol-5-yl)carbamate, MS (apci) m/z=478.1(M+H).

Step C: Preparation of2-(4-chloro-5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazol-3-yl)ethylacetate

To a solution of(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride (Preparation F, 52 mg, 0.158 mmol) in DMA (0.6 mL) wasadded DIEA (0.110 mL, 0.630 mmol) was added a mixture of2-(4-chloro-5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yl)ethylacetate and phenyl(4-chloro-3-(2-((phenoxycarbonyl)oxy)ethyl)-1-phenyl-1H-pyrazol-5-yl)carbamate(63 mg). The reaction mixture was stirred at ambient temperature for 2hours then purified directly by reverse-phase column chromatography,eluting with 5-80% acetonitrile/water and collecting Peak 1 to affordthe title compound as an orange solid (21.8 mg). MS (apci) m/z=562.2(M+H).

Example 449

1-(4-chloro-3-(2-hydroxyethyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureaStep A: Preparation of2-(4-chloro-5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazol-3-yl)ethylphenyl carbonate

The reaction mixture from Example 448, Step C, was purified directly byreverse-phase column chromatography, eluting with 5-80%acetonitrile/water and collecting Peak 2 to afford the title compound asa pale yellow gum (28 mg). MS (apci) m/z=640.2 (M+H).

Step B: Preparation of1-(4-chloro-3-(2-hydroxyethyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

To a solution of2-(4-chloro-5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazol-3-yl)ethylphenyl carbonate (28 mg, 0.044 mmol) in THF (2 mL) and MeOH (1 mL) wasadded aqueous LiOH (2M, 0.066 mL, 0.132 mmol). The reaction mixture wasstirred at ambient temperature for 2 hours then diluted with aqueous HCl(2M, 0.06 mL) and H₂O (5 mL), and extracted with DCM (10 mL) then 10:90MeOH/DCM (2×10 mL). The combined organic extracts were dried (MgSO₄),filtered and concentrated. The crude product was purified by silicacolumn chromatography eluting with 0-10% MeOH/DCM to afford the productas an off-white solid (14 mg, 61% yield). MS (apci) m/z=520.2 (M+H).

Example 450

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(cis-3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureaStep A: Preparation of cis- andtrans-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

To a solution of(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride (Preparation F, 67 mg, 0.204 mmol) in DMA (1 mL) andDIEA (0.142 mL, 0.815 mmol) was added phenyl3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate(Intermediate 209; 74 mg, 0.204 mmol) and the reaction mixture asstirred at ambient temperature for 1 hour. The reaction mixture wasdirectly purified by reverse-phase column chromatography, eluting with5-70% acetonitrile/water to yield the product as a white solid (59 mg,55% yield). MS (apci) m/z=526.3 (M+H).

Step B: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(cis-3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

The mixture of cis- andtrans-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea(55 mg, 0.105 mmol) was separated by preparatory HPLC on a benzamidecolumn (Princeton Analytical, 4.6 mm×250 mm, 5 μm), eluted with 10%EtOH/hexanes. Peak 1 was collected to afford the title compound as awhite solid (21.1 mg, 38% yield). MS (apci) m/z=526.3 (M+H). ¹H NMR(d₆-DMSO) δ 7.79 (br s, 1H), 7.42 (m, 4H), 7.30 (m, 3H), 7.06 (m, 1H),6.70 (d, 1H), 5.06 (d, 1H), 4.04 (m, 2H), 3.43 (t, 2H), 3.24 (s, 3H),3.05 (m, 2H), 2.85 (m, 2H), 2.47-2.66 (m, 6H), 2.08 (m, 2H), 1.77 (s,3H).

Example 451

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(trans-3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

A mixture of cis and trans hydroxycyclobutyl diastereomers1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea(Example 450, Step A, 55 mg, 0.105 mmol) was separated by preparatoryHPLC on a benzamide column (Princeton Analytical, 4.6 mm×250 mm, 5 μm),eluted with 10% EtOH/hexanes. Peak 2 was collected to afford the titlecompound as a white solid (27.5 mg, 50% yield). MS (apci) m/z=526.3(M+H). ¹H NMR (d₆-DMSO) δ 7.80 (br s, 1H), 7.42 (m, 4H), 7.31 (m, 3H),7.06 (m, 1H), 6.70 (d, 1H), 5.02 (d, 1H), 4.33 (m, 1H), 4.04 (m, 1H),3.43 (t, 2H), 3.34 (m, 1H), 3.24 (s, 3H), 3.05 (m, 2H), 2.88 (t, 1H),2.43-2.67 (m, 6H), 2.19 (m, 2H), 1.74 (s, 3H).

Example 452

1-(4-chloro-3-(cis-3-hydroxycyclobutyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureaStep A: cis- andtrans-1-(4-chloro-3-(3-hydroxycyclobutyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the method described in Example 450, Step A,replacing phenyl3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate withphenyl(4-chloro-3-(3-hydroxycyclobutyl)-1-phenyl-1H-pyrazol-5-yl)carbamate(Intermediate 238) in Step A to afford the product as a mixture of cisand trans hydroxycyclobutyl diastereomers. MS (apci) m/z=546.2 (M+H).

Step B: Preparation of1-(4-chloro-3-(cis-3-hydroxycyclobutyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

To a mixture of cis and trans hydroxycyclobutyl diastereomers1-(4-chloro-3-(3-hydroxycyclobutyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea(41 mg, 0.075 mmol) was separated by preparatory HPLC on a DEAP column(Princeton Analytical, 4.6 mm×250 mm, 5 μm), eluted with 10%EtOH/hexanes. Peak 1 was collected to afford the title compound as awhite solid (10.2 mg, 25% yield). MS (apci) m/z=546.2 (M+H). ¹H NMR(CDCl₃) 7.50 (d, 2H), 7.41 (t, 2H), 7.30 (m, 1H), 7.05 (m, 1H), 6.97 (m,1H), 6.86 (m, 1H), 5.48 (m, 1H), 4.30 (m, 1H), 3.43 (br m, 2H), 3.33 (m,1H), 3.25 (br m, 2H), 3.10 (m, 2H), 2.96 (br m, 1H), 2.60-2.83 (m 5H),2.33 (m, 3H).

Example 453

1-(4-chloro-3-((1r,3S)-3-hydroxycyclobutyl)-1-phenyl-1H-pyrazol-5-yl)-3-(trans-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

A mixture of cis- andtrans-1-(4-chloro-3-(3-hydroxycyclobutyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea(Example 452, Step A, 41 mg, 0.075 mmol) was separated by preparatoryHPLC on a DEAP column (Princeton Analytical, 4.6 mm×250 mm, 5 μm),eluted with 10% EtOH/hexanes. Peak 1 was collected to afford the titlecompound as a white solid (16.4 mg, 40% yield). MS (apci) m/z=546.2(M+H). ¹H NMR (CDCl₃) 7.51 (d, 2H), 7.41 (t, 2H), 7.33 (m, 1H), 7.04 (m,1H), 6.96 (m, 1H), 6.85 (m, 1H), 5.53 (br d, 1H), 4.65 (m, 1H), 3.60 (m,1H), 3.41 (br m, 2H), 3.25 (br m, 5H), 3.08 (br m, 1H), 2.89 (br m, 1H),2.57-2.77 (m, 7H), 2.37 (m, 3H).

Example 454

1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(cis-3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureaStep A: Preparation of cis- andtrans-1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the method described in Example 450, Step A,replacing(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride with(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride (Preparation K) in Step A to afford the product as amixture of cis and trans hydroxycyclobutyl diastereomers. MS (apci)m/z=508.3 (M+H).

Step B: Preparation of 1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(cis-3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

The mixture of cis- andtrans-1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea(49 mg, 0.096 mmol) was separated by supercritical fluid chromatography(SFC) on a cyano column (YMC-Pack CN, 250×20 mm, 10 μm), mobile phase95% CO₂ and 5% 80/20/0.1 MeOH/IPA/diethylamine. Peak 1 was collected toafford the title compound as a white solid (16.4 mg, 34% yield). MS(apci) m/z=508.2 (M+H). ¹H NMR (d₆-DMSO) δ 7.85 (br s, 1H), 7.42 (m,4H), 7.28 (m, 3H), 7.10 (t, 2H), 6.75 (br d, 1H), 5.06 (br s, 1H), 4.04(m, 2H), 3.42 (t, 2H), 3.24 (s, 3H), 3.06 (m, 2H), 2.84 (m, 2H),2.46-2.64 (m, 6H), 2.08 (m, 2H), 1.76 (s, 3H).

Example 455

1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(trans-3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

A mixture of cis- andtrans-1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea(Example 454, Step A, 49 mg, 0.096 mmol) was separated by supercriticalfluid chromatography (SFC) on a cyano column (YMC-Pack CN, 250×20 mm, 10μm), mobile phase 95% CO₂ and 5% 80/20/0.1 MeOH/IPA/diethylamine. Peak 2was collected to afford the title compound as a white solid (19.0 mg,39% yield). MS (apci) m/z=508.2 (M+H). ¹H NMR (d₆-DMSO) δ 7.86 (br s,1H), 7.42 (m, 4H), 7.28 (m, 3H), 7.10 (t, 2H), 6.75 (br d, 1H), 5.03 (brs, 1H), 4.33 (m, 1H), 4.03 (m, 1H), 3.42 (t, 2H), 3.34 (m, 1H), 3.24 (s,3H), 3.07 (m, 2H), 2.84 (t, 1H), 2.43-2.64 (m, 6H), 2.19 (m, 2H), 1.73(s, 3H).

Example 456

1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(cis-3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureaStep A: Preparation of cis- andtrans-1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-meth-oxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the method described in Example 450, Step A,replacing(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride with(3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride (Preparation E) in Step A to afford the product as amixture of cis and trans hydroxycyclobutyl diastereomers. MS (apci)m/z=526.3 (M+H).

Step B: Preparation of1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(cis-3-hydroxycyclobutyl)-4-methyl-1-phenyl-H-pyrazol-5-yl)urea

The mixture of cis and trans hydroxycyclobutyl diastereomers1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea(53 mg, 0.10 mmol) was separated by supercritical fluid chromatography(SFC) on a cyano column (YMC-Pack CN, 250×20 mm, 10 μm), mobile phase95% CO₂ and 5% 80/20/0.1 MeOH/IPA/diethylamine. Peak 1 was collected toafford the title compound as a white solid (17.6 mg, 33% yield). MS(apci) m/z=526.2 (M+H). ¹H NMR (d₆-DMSO) δ 7.95 (br s, 1H), 7.45 (d,2H), 7.39 (t, 2H), 7.28 (t, 1H), 7.05 (tt, 1H), 6.97 (m, 2H), 6.85 (m,1H), 5.08 (br s, 1H), 4.05 (m, 2H), 3.43 (t, 2H), 3.24 (s, 3H), 3.08 (m,1H), 3.02 (m, 1H), 2.89 (m, 1H), 2.84 (m, 1H), 2.45-2.65 (m, 6H), 2.08(m, 2H), 1.77 (s, 3H).

Example 457

1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(trans-3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

A mixture of cis and trans hydroxycyclobutyl diastereomers1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea(Example 456, Step A, 53 mg, 0.10 mmol) was separated by supercriticalfluid chromatography (SFC) on a cyano column (YMC-Pack CN, 250×20 mm, 10μm), mobile phase 95% CO₂ and 5% 80/20/0.1 MeOH/IPA/diethylamine. Peak 2was collected to afford the title compound as a white solid (20.7 mg,39% yield). MS (apci) m/z=526.2 (M+H). ¹H NMR (d₆-DMSO) δ 7.96 (br s,1H), 7.46 (d, 2H), 7.40 (t, 2H), 7.28 (t, 1H), 7.05 (tt, 1H), 6.97 (m,2H), 6.85 (m, 1H), 5.04 (br s, 1H), 4.34 (m, 1H), 4.06 (m, 1H), 3.43 (t,2H), 3.35 (m, 1H), 3.24 (s, 3H), 3.09 (q, 1H), 3.02 (t, 1H), 2.90 (t,1H), 2.44-2.66 (m, 6H), 2.19 (m, 2H), 1.74 (s, 3H).

Example 458

5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yyl)ureido)-4-methyl-1-phenyl-1H-pyrazole-3-carboxylicacid

To a solution of ethyl5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxy-ethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazole-3-carboxylate(Example 291; 333 mg, 6.21 mmol) in THF (4 mL) and MeOH (2 mL) was addedaqueous LiOH (2M, 0.95 mL, 1.89 mmol). The reaction mixture was stirredat ambient temperature for 4 hours, then partially concentrated underreduced pressure, then neutralized with aqueous HCl (1M, 1 mL). Thesuspension was filtered and the white precipitate was collected toafford the title compound as a white solid (247 mg, 78% yield). MS(apci) m/z=500.2 (M+H).

Example 459

5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-N,4-dimethyl-1-phenyl-1H-pyrazole-3-carboxamide

To a solution of5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazole-3-carboxylicacid (Example 458, 25 mg, 0.050 mmol) in DMF (0.5 mL) were added DIEA(0.026 mL, 0.150 mmol), methanamine hydrochloride (6.8 mg, 0.100 mmol),then HATU (20.9 mg, 0.055 mmol). The reaction mixture was stirred atambient temperature for 19 hours. The reaction mixture was directlypurified by reverse-phase column chromatography, eluting with 5-60%acetonitrile/water to afford the product as a white solid (13.5 mg, 53%yield). MS (apci) m/z=513.3 (M+H).

Example 460

5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-N,N,4-trimethyl-1-phenyl-1H-pyrazole-3-carboxamide

Prepared according to the method described in Example 459 replacingmethanamine hydrochloride with dimethylamine (2M in THF) to afford theproduct as a white solid (13.0 mg, 49% yield). MS (apci) m/z=527.2(M+H).

Example 461

5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-N-ethyl-4-methyl-1-phenyl-1H-pyrazole-3-carboxamide

Prepared according to the method described in Example 459 replacingmethanamine hydrochloride with ethanamine (2M in THF) to afford theproduct as a white solid (11.2 mg, 48% yield). MS (apci) m/z=527.2(M+H).

Example 462

5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-N-isopropyl-4-methyl-1-phenyl-1H-pyrazole-3-carboxamide

Prepared according to the method described in Example 459 replacingmethanamine hydrochloride with propan-2-amine to afford the product as awhite solid (5.6 mg, 24% yield). MS (apci) m/z=541.3 (M+H).

Example 463

5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazole-3-carboxamide

A solution of1-(3-cyano-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea(Example 349, 25 mg, 0.52 mmol) in concentrated H₂SO₄ (0.2 mL) wasstirred at ambient temperature for 20 hours. The reaction mixture wascooled to 0° C. and neutralized by the addition of aqueous NaOH (15 wt%, 4 mL), then extracted 10% MeOH/DCM (3×10 mL), and the combinedorganic extracts were washed with brine, dried (MgSO₄), filtered andconcentrated under reduced pressure. The crude product was purified byreverse-phase column chromatography, eluting with 5-60%acetonitrile/water to yield the product as a white solid (1.4 mg, 5%yield). MS (apci) m/z=499.2 (M+H).

Example 464

1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-(hydroxymethyl)-1-phenyl-1H-pyrazol-5-yl)ureaStep A: Preparation of ethyl5-(3-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-3-ethoxy-1-phenyl-1H-pyrazole-4-carboxylate

To a solution of ethyl5-amino-3-ethoxy-1-phenyl-1H-pyrazole-4-carboxylate (Intermediate 174,68 mg, 0.25 mmol) in DCM (1 mL) was added DIEA (0.086 mL, 0.49 mmol)then triphosgene (26 mg, 0.086 mmol). The reaction mixture was stirredat ambient temperature for 2 hours, then additional triphosgene (26 mg,0.086 mmol) was added. The reaction mixture was stirred at ambienttemperature for 22 hours, and then additional triphosgene (26 mg, 0.086mmol) was added. The reaction mixture was stirred at ambient temperaturefor another 5 hours, then a solution of (3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride(Preparation E, 81 mg, 0.25 mmol) and DIEA (0.13 mL, 0.74 mmol) in DCM(0.5 mL) was added. The reaction mixture was stirred at ambienttemperature for 1 hour, then concentrated under reduced pressure andpurified by reverse-phase column chromatography, eluting with 5-70%acetonitrile/water to yield the product as a white solid (12 mg, 9%yield). MS (apci) m/z=558.3 (M+H).

Step B: Preparation of1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-(hydroxymethyl)-1-phenyl-1H-pyrazol-5-yl)urea

To a solution of ethyl5-(3-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-3-ethoxy-1-phenyl-1H-pyrazole-4-carboxylate(18 mg, 0.032 mmol) in THF (2 mL) under N₂ cooled to 0° C. was addedLiAlH₄ (1M bis-THF in toluene, 0.032 mL, 0.032 mmol). The reactionmixture was stirred at 0° C. for 2 hours, then at ambient temperaturefor 90 minutes, then cooled to 0° C. and quenched by addition of H₂O(0.005 mL), 5 μL aqueous NaOH (1M, 0.005 mL), then H₂O (0.015 mL),stirred for 10 minutes, then filtered, rinsed with THF (2×5 mL), andconcentrated. The crude product was purified by preparatory TLC (0.5 mmplate, eluted with 5% MeOH/DCM) to afford the product as a colorlessresidue (1.6 mg, 10% yield). MS (apci) m/z=516.3 (M+H).

Example 465

1-((3S,4R)-4-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)urea

The racemic mixture1-(trans-4-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)urea (Example 293, 30 mg, 0.054 mmol) wasseparated by chiral HPLC (Chiralcel OD column) eluted with 10%EtOH/hexanes. Peak 1 was collected to afford the title compound as awhite solid (9.8 mg, 33% yield). MS (apci) m/z=552.2 (M+H).

Example 466

1-((3S,4R)-4-(4-chloro-3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)urea

The racemic mixture1-(trans-4-(4-chloro-3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)urea(Example 294, 42 mg, 0.076 mmol) was separated by chiral HPLC (ChiralcelOD column) eluted with 10% EtOH/hexanes. Peak 1 was collected to affordthe title compound as a white solid (17.1 mg, 41% yield). MS (apci)m/z=552.2 (M+H).

Example 467

1-((3S,4R)-4-(3-chloro-5-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)urea

The racemic mixture1-(trans-4-(3-chloro-5-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)urea(Example 295, 32 mg, 0.058 mmol) was separated by chiral HPLC (ChiralpakIA column) eluted with 15% EtOH/hexanes. Peak 2 was collected to affordthe title compound as a white solid (12.5 mg, 39% yield). MS (apci)m/z=552.2 (M+H).

Example 468

methyl2-((3R,4S)-3-(3,4-difluorophenyl)-4-(3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureido)pyrrolidin-1-yl)acetate

Prepared according to the method described in Example 191, replacing2-bromoethanol with methyl 2-bromoacetate in Step A and replacing phenyl3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate with phenyl3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared accordingto Example 1, Step A, starting with Intermediate P135) in Step C toafford the product as a white solid (23 mg, 50% yield). MS (apci)m/z=514.2 (M+H).

Example 469

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(3,3,3-trifluoro-2-hydroxypropyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-H-pyrazol-5-yl)urea

Prepared according to the method described in Example 191, replacing2-bromoethanol with 3-bromo-1,1,1-trifluoropropan-2-ol in Step A andreplacing phenyl 3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate withphenyl 3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (preparedaccording to Example 1, Step A, starting with Intermediate P135) in StepC to afford the product as a white solid (38 mg, 78% yield). MS (apci)m/z=554.2 (M+H).

Example 470

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-hydroxypropyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the method described in Example 191, replacing2-bromoethanol with 1-chloropropan-2-ol (Aldrich, 70% purity with <25%of 2-chloropropan-1-ol) in Step A and replacing phenyl3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate with phenyl3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared accordingto Example 1, Step A starting with Intermediate P135) in Step C toafford the product as a white solid (10 mg, 53% yield). MS (apci)m/z=500.2 (M+H).

Example 471

1-((3S,4R)-1-(2-cyanoethyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the method described in Example 191, replacingacrylonitrile with 1-chloropropan-2-ol in Step A and replacing phenyl3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate with phenyl3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared accordingto Example 1, Step A, starting with Intermediate P135) in Step C toafford the product as a white solid (16 mg, 59% yield). MS (apci)m/z=459.3 (M+H).

Example 472

2-((3R,4S)-3-(3,4-difluorophenyl)-4-(3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureido)pyrrolidin-1-yl)-N-methylacetamideStep A: Preparation of2-((3R,4S)-3-(3,4-difluorophenyl)-4-(3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureido)pyrrolidin-1-yl)aceticacid

To a solution of methyl2-((3R,4S)-3-(3,4-difluorophenyl)-4-(3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureido)pyrrolidin-1-yl)acetate(Example 468; 15 mg, 0.029 mmol) in THF (0.8 mL) and MeOH (0.4 mL) wasadded aqueous LiOH (2M, 0.044 mL, 0.088 mmol). The reaction mixture wasstirred at ambient temperature for 3 hours, then diluted with aqueousHCl (1M, 1 mL) and brine (2 mL) and extracted with DCM (2×5 mL). Thecombined organic extracts were dried (MgSO₄), filtered and concentratedafford the product as an off-white solid (13.0 mg, 89% yield). MS (apci)m/z=500.2 (M+H).

Step B: Preparation of2-((3R,4S)-3-(3,4-difluorophenyl)-4-(3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureido)pyrrolidin-1-yl)-N-methylacetamide

To a suspension of2-((3R,4S)-3-(3,4-difluorophenyl)-4-(3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureido)pyrrolidin-1-yl)acetic acid (7.4 mg, 0.015 mmol) in DMF (0.5 mL) wereadded N-methylmorpholine (0.005 mL, 0.044 mmol), methylamine (2M in THF,0.009 mL, 0.018 mmol) then HATU (6.8 mg, 0.018 mmol). The reactionmixture was stirred at ambient temperature for 19 hours then purifieddirectly by reverse-phase column chromatography, eluting with 5-70%acetonitrile/water to afford the title compound as a pale white solid(4.2 mg, 55% yield). MS (apci) m/z=513.3 (M+H).

Example 473

1-(1-cyclohexyl-3,4-dimethyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureaStep A: Preparation of 1-cyclohexyl-3,4-dimethyl-1H-pyrazol-5-amine

To a suspension of cyclohexylhydrazine hydrochloride (0.465 g, 3.09mmol) in ethanol (30 mL) was added 2-oxocyclopentanecarbonitrile (0.30g, 3.09 mmol). The mixture was heated to reflux for 18 hours, thencooled to ambient temperature and concentrated in vacuo. The residue waspartitioned between saturated NaHCO₃ (30 mL) and EtOAc (30 mL). Theaqueous layer was extracted with EtOAc (2×20 mL) and the combinedorganic phases were washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated to afford1-cyclohexyl-3,4-dimethyl-1H-pyrazol-5-amine (0.523 g, 88% yield) as acream solid. ¹H NMR (CDCl₃) δ 3.78-3.93 (m, 1H), 3.13 (br s, 2H), 2.12(s, 3H), 1.85-1.95 (m, 6H), 1.83 (s, 3H), 1.63-1.73 (m, 1H), 1.18-1.44(m, 3H) ppm.

Step B: Preparation of phenyl(1-cyclohexyl-3,4-dimethyl-1H-pyrazol-5-yl)carbamate

To a solution of 1-cyclohexyl-3,4-dimethyl-1H-pyrazol-5-amine (200 mg,1.04 mmol) in EtOAc (5 mL) was added 2N NaOH (1.04 mL, 2.1 mmol)followed by phenyl chloroformate (182 L, 1.45 mmol). The mixture wasstirred at ambient temperature for 5 hours then diluted with water (30mL) and extracted with EtOAc (3×20 mL). The combined organic phases werewashed with saturated NaHCO₃ (20 mL) and brine (20 mL) then dried overNa₂SO₄ and concentrated in vacuo to afford phenyl(1-cyclohexyl-3,4-dimethyl-1H-pyrazol-5-yl)carbamate as a pale purplefoam which was used without purification assuming quantitative yield.

Step C: Preparation of1-(1-cyclohexyl-3,4-dimethyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

To a solution of(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation F) (50 mg, 0.15 mmol) and phenyl(1-cyclohexyl-3,4-dimethyl-1H-pyrazol-5-yl)carbamate (52 mg, 0.17 mmol)in DMA (2 mL) was added DIEA (93 μL, 0.53 mmol). The mixture was stirredat ambient temperature for 18 hours then partitioned between saturatedNH₄Cl (20 mL) and EtOAc (20 mL) and the aqueous layer extracted withEtOAc (2×10 mL). The combined organic phases were washed with water(5×10 mL) and brine (10 mL) then dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica columnchromatography, eluting with 2% MeOH/DCM to yield the title compound (42mg, 58% yield) as a colorless glass. MS (apci) m/z=476.3 (M+H).

Example 474

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxy-2-(hydroxymethyl)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureaStep A: Preparation of (2,2-dimethyl-1,3-dioxan-5-yl)methanol

To a suspension of 2-(hydroxymethyl)propane-1,3-diol (5.0 g, 47.1 mmol)in THF (100 mL) was added p-toluenesulfonic acid monhydrate (269 mg,1.41 mmol) followed by 2,2-dimethoxypropane (6.72 mL, 54.7 mmol). Themixture was stirred at ambient temperature for 3 hours then a further200 mg of p-toluenesulfonic acid monhydrate added and stirring continuedfor a further 60 hours. The solution was treated with triethylamine (3mL) then concentrated in vacuo. The residue was purified by silicacolumn chromatography eluting with 5% MeOH/DCM to afford(2,2-dimethyl-1,3-dioxan-5-yl)methanol (5.04 g, 73% yield) as acolorless liquid. ¹H NMR (CDCl₃) δ 4.02 (dd, J=12.0, 4.1 Hz, 2H),3.74-3.80 (m, 4H), 1.90 (t, J=5.1 Hz, 1H), 1.80-1.88 (m, 1H), 1.45 (s,3H), 1.40 (s, 3H) ppm.

Step B: Preparation of (2,2-dimethyl-1,3-dioxan-5-yl)methylmethanesulfonate

To a solution of (2,2-dimethyl-1,3-dioxan-5-yl)methanol (1.0 g, 6.84mmol) in DCM (30 mL) at 0° C. was added triethylamine (1.43 mL, 10.3mmol) followed by mesyl chloride (0.58 mL, 7.52 mmol). The mixture wasallowed to warm slowly to ambient temperature with stirring over 18hours. The mixture was partitioned between 0.5 M HCl (40 mL) and DCM (20mL) and the aqueous layer was extracted with DCM (2×20 mL). The combinedorganic phases were washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated to afford (2,2-dimethyl-1,3-dioxan-5-yl)methylmethanesulfonate (1.29 g, 84% yield) as a colorless oil. ¹H NMR (CDCl₃)δ 4.42 (d, J=7.3 Hz, 2H), 4.08 (dd, J=12.5, 3.5 Hz, 2H), 3.77 (dd,J=12.5, 3.9 Hz, 2H), 3.04 (s, 3H), 1.98-2.03 (m, 1H), 1.46 (s, 3H), 1.39(s, 3H) ppm.

Step C: Preparation of3-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-amine

To a solution of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3 (2H)-one(Intermediate P135, Step A; 500 mg, 2.64 mmol) in DMF (5 mL) was addedK₂CO₃ (1.10 g, 7.93 mmol) followed by a solution of(2,2-dimethyl-1,3-dioxan-5-yl)methyl methanesulfonate (711 mg, 3.17mmol) in DMF (2 mL). The mixture was stirred at 50° C. for 18 hours thencooled, treated with water (30 mL) and extracted with EtOAc (3×20 mL).The combined organic phases were washed with water (5×10 mL) and brine(10 mL) then dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by silica column chromatography eluting with 4:1 to2:1 hexanes/EtOAc, to afford3-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-amine(198 mg, 24%) as a yellow gum. MS (apci) m/z=318.1 (M+H).

Step D: Preparation of phenyl(3-(3-hydroxy-2-(hydroxymethyl)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate

To a solution of3-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-amine(198 mg, 0.62 mmol) in EtOAc (5 mL) was added 2M NaOH (780 μL, 1.56mmol) followed by phenyl chloroformate (117 μL, 0.94 mmol). The mixturewas stirred at ambient temperature for 18 hours then partitioned betweenwater (20 mL) and EtOAc (20 mL) and the aqueous layer extracted withEtOAc (2×20 mL). The combined organic phases were washed with saturatedNaHCO₃ (20 mL) and brine (20 mL) then dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica columnchromatography eluting with 2-4% MeOH/DCM to afford(3-(3-hydroxy-2-(hydroxymethyl)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate(75 mg, 30% yield) as a cream foam. MS (apci) m/z=398.2 (M+H).

Step E: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxy-2-(hydroxymethyl)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the method of Example 473, Step C, replacingphenyl (1-cyclohexyl-3,4-dimethyl-1H-pyrazol-5-yl)carbamate with(3-(3-hydroxy-2-(hydroxymethyl)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate. The material waspurified by silica column chromatography eluting with 2-5% MeOH/DCM toafford the title compound (26 mg, 55% yield) as a colorless glass. MS(apci) m/z=560.3 (M+H).

Example 475

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl)ureaStep A: Preparation of4-methyl-1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-amine

Prepared according to the method of Example 474, Step C, replacing(2,2-dimethyl-1,3-dioxan-5-yl)methyl methanesulfonate with1,1,1-trifluoro-2-iodoethane. MS (apci) m/z=272.1 (M+H).

Step B: Preparation of phenyl(4-methyl-1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl)carbamate

Prepared according to the method of Example 474, Step D, replacing3-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-aminewith 4-methyl-1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-amine. MS(apci) m/z=392.1 (M+H).

Step C: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl)urea

Prepared according to the method of Example 473, Step C, replacingphenyl (1-cyclohexyl-3,4-dimethyl-1H-pyrazol-5-yl)carbamate with phenyl(4-methyl-1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl)carbamate.The material was purified by silica column chromatography eluting with5% MeOH/DCM followed by prep HPLC (5-95% ACN/H₂O/0.1% TFA, over 20minutes) to afford the title compound (16 mg, 38% yield) afterextractive work-up (DCM/1N NaOH) as a white solid. MS (apci) m/z=554.2(M+H).

Example 476

1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl)urea

Prepared according to the method of Example 475, replacing(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation F) with(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride (Preparation K). The material was purified by silicacolumn chromatography eluting with 2% MeOH/DCM to afford the titlecompound (56 mg, 65% yield) as a white solid. MS (apci) m/z=536.2 (M+H).

Example 477

1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl)urea

Prepared according to the method of Example 475, replacing(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation F) with(3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminetrifluoroacetate (Preparation E). The material was purified by silicacolumn chromatography eluting with 2% MeOH/DCM to afford the titlecompound (53 mg, 63% yield) as a colorless glass. MS (apci) m/z=554.2(M+H).

Example 478

1-(3-(2,2-difluoroethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the method of Example 475, replacing1,1,1-trifluoro-2-iodoethane with 1,1-difluoro-2-iodoethane in Step A.The material was purified by silica column chromatography eluting with2% MeOH/DCM to afford the title compound (55 mg, 68% yield) as a whitesolid. (MS (apci) m/z=536.2 (M+H).

Example 479

1-(4-chloro-1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureaStep A: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl)urea

Prepared according to the method of Example 475, replacing5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (Intermediate P135, StepA) with 5-amino-1-phenyl-1H-pyrazol-3(2H)-one (Intermediate P136,

Step A) Step B: Preparation of1-(4-chloro-1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

To a solution of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl)urea(50 mg, 0.09 mmol) in DCM (1 mL) was added N-chlorosuccinimide (15 mg,0.11 mmol) followed by pyridin-1-ium 4-methylbenzenesulfonate (2 mg,0.009 mmol). The mixture was stirred at ambient temperature for 18 hoursthen treated with a further 5 mg of N-chlorosuccinimide and stirred for2.5 hours. The mixture was partitioned between saturated NaHCO₃ (20 mL)and DCM (20 mL) and the aqueous layer was extracted with DCM (2×10 mL).The combined organic phases were washed with brine (10 mL), dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by silicacolumn chromatography eluting with 2.5% MeOH/DCM to afford the titlecompound (28 mg, 53% yield) as a pale yellow foam. MS (apci) m/z=574.2(M+H).

Example 480

1-(4-chloro-1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureaStep A: Preparation of 1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine

Prepared according to the method of Example 473, Step A, replacingcyclohexylhydrazine hydrochloride with phenylhydrazine hydrochloride and2-oxocyclopentanecarbonitrile with 3-oxo-3-(pyridin-2-yl)propanenitrile.MS (apci) m/z=237.1 (M+H).

Step B: Preparation of4-chloro-1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine

A solution of 1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine (300 mg, 1.27mmol) was dissolved in DCM (20 mL) and treated with N-chlorosuccinimide(187 mg, 1.40 mmol) followed by pyridin-1-ium 4-methylbenzenesulfonate(32 mg, 0.13 mmol). The solution was stirred at ambient temperature for3 hours then partitioned between DCM (20 mL) and saturated NaHCO₃ (20mL) and the aqueous layer extracted with DCM (2×20 mL). The combinedorganic phases were washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by silicacolumn chromatography eluting with 2:1 hexanes/EtOAc to afford4-chloro-1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine (211 mg, 61%) as apink foam. MS (apci) m/z=271.0 (M+H).

Step C: Preparation of1-(4-chloro-1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

To a solution of 4-chloro-1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine(37 mg, 0.14 mmol) in DCM (2 mL) was added triphosgene (21 mg, 0.07mmol) followed by DIEA (72 μL, 0.41 mmol). The mixture was stirred atambient temperature for 1 hour then treated with(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation F) (50 mg, 0.15 mmol) followed by DIEA (72 μL, 0.41 mmol).After stirring for a further 18 hours the mixture was partitionedbetween saturated NH₄Cl (20 mL) and DCM (20 mL) and the aqueous layerextracted with DCM (2×10 mL). The combined organic phases were washedwith brine (20 mL), dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by silica column chromatography elutingwith 2.5% MeOH/DCM followed by reverse phase HPLC purification (5-95%ACN/water/0.5% TFA over 20 minutes). The title compound (10 mg, 13%yield) was obtained after aqueous work-up (1N NaOH/DCM) as a whitesolid. MS (apci) m/z=553.2 (M+).

Example 481

1-(4-chloro-1-phenyl-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the method of Example 480 replacing3-oxo-3-(pyridin-2-yl)propanenitrile with3-oxo-3-(pyridin-4-yl)propanenitrile in Step A. The material waspurified by silica column chromatography eluting with 2% MeOH/DCMfollowed by reverse phase HPLC purification (5-95% ACN/water/0.5% TFAover 20 minutes). The title compound (3 mg, 4% yield) was obtained afteraqueous work-up (1N NaOH/DCM) as a white solid. MS (apci) m/z=553.2(M+).

Example 482

1-(4-chloro-1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureaStep A: Preparation of 1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-amine

Prepared according to the method of Example 480, Step A, replacing3-oxo-3-(pyridin-2-yl)propanenitrile with3-oxo-3-(pyridin-3-yl)propanenitrile. MS (apci) m/z=237.1 (M+H).

Step B: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)urea

To a solution of 1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-amine (50 mg,0.21 mmol) and CDI (72 mg, 0.44 mmol) in DMF (2 mL) was added DIEA (147μL, 0.85 mmol) and the mixture stirred at 50° C. for 4 hours. To thecooled mixture was added(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation F) (146 mg, 0.44 mmol) and DIEA (147 μL, 0.85 mmol) andstirring was continued at ambient temperature for 18 hours. The mixturewas partitioned between saturated NH₄Cl (20 mL) and EtOAc (20 mL) andthe aqueous layer extracted with EtOAc (2×10 mL). The combined organicphases were washed with water (5×10 mL) and brine (10 mL) then driedover Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica column chromatography eluting with 5% MeOH/DCM toafford1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)urea(80 mg, 73%) as a white solid. MS (apci) m/z=519.3 (M+H).

Step C: Preparation of1-(4-chloro-1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

To a solution of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)urea(40 mg, 0.08 mmol) in DCM (1 mL) was added N-chlorosuccinimide (12 mg,0.09 mmol) followed by pyridin-1-ium 4-methylbenzenesulfonate (2 mg,0.008 mmol). The mixture was stirred at ambient temperature for 18 hoursthen partitioned between saturated NaHCO₃ (20 mL) and DCM (20 mL) andthe aqueous layer extracted with DCM (2×10 mL). The combined organicphases were washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica columnchromatography eluting with 2.5-5% MeOH/DCM to afford the title compound(16 mg, 38% yield) as a pale yellow solid. MS (apci) m/z=553.2 (M+).

Example 483

1-(4-bromo-1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the method of Example 482, replacingN-chlorosuccinimide with N-bromosuccinimide in Step C. The material waspurified by silica column chromatography eluting with 3% MeOH/DCM toafford the title compound (31 mg, 67% yield) as a yellow solid. MS(apci) m/z=597.2 (M+H).

Example 484

1-(4-bromo-1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureaStep A: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl)urea

Prepared according to the method of Example 480, replacing4-chloro-1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine with1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine in Step C. MS (apci)m/z=519.2 (M+H).

Step B: Preparation of1-(4-bromo-1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the method of Example 483, replacing1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)ureawith1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl)ureain Step C. Material was purified by silica column chromatography elutingwith 2.5-5% MeOH/DCM to afford the title compound (14 mg, 40% yield) asa colorless glass. MS (apci) m/z=597.2 (M+).

Example 485

1-(4-chloro-3-phenyl-1-(pyridin-3-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the procedure of Example 482, replacing3-oxo-3-(pyridin-3-yl)propanenitrile with 3-oxo-3-phenylpropanenitrileand phenylhydrazine hydrochloride with 3-hydrazinylpyridinehydrochloride in Step A. Material was purified by silica columnchromatography eluting with 2.5% MeOH/DCM to afford the title compound(22 mg, 49% yield) as a beige solid. MS (apci) m/z=553.2 (M+).

Example 486

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)ureaStep A: Preparation of 2-methyl-3-oxo-3-(pyridin-3-yl)propanenitrile

A solution of LiHMDS (13.6 mL, 1.0M/THF, 13.6 mmol) was cooled to −78°C. under N₂ atmosphere and treated dropwise with propionitrile (991 μL,13.9 mmol). The resulting yellow slurry was stirred at this temperaturefor 2 hours then treated dropwise with a solution of ethyl nicotinate(1.0 g, 6.62 mmol) in THF (5 mL) over 10 minutes. The mixture wasallowed to warm slowly to ambient temperature over 18 hours then pouredinto ice-cold water (100 mL) and extracted with Et₂O (2×30 mL). Theaqueous phase was cooled in ice, acidified to pH 5 with 1N HCl andextracted with DCM (3×30 mL). The combined DCM extracts were washed withbrine (30 mL), dried over Na₂SO₄, filtered and concentrated to afford2-methyl-3-oxo-3-(pyridin-3-yl)propanenitrile (1.06 g, 100% yield) as ayellow oil. MS (apci) m/z=161.1 (M+H).

Step B: Preparation of4-methyl-1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-amine

A suspension of 2-methyl-3-oxo-3-(pyridin-3-yl)propanenitrile (1.06 g,6.62 mmol) and phenylhydrazine hydrochloride (1.05 g, 7.28 mmol) in EtOH(30 mL) was stirred at reflux for 18 hours then cooled to ambienttemperature. The mixture was concentrated then treated with saturatedNaHCO₃ (50 mL) and extracted with DCM (3×30 mL). The combined organicphases were washed with brine (30 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica columnchromatography eluting with 1:1 to 1:2 hexanes/EtOAc, to afford4-methyl-1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-amine (984 mg, 59%yield) as a pale yellow foam. MS (apci) m/z=251.1 (M+H).

Step C: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)urea

To a solution of 4-methyl-1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-amine(100 mg, 0.40 mmol) in DCM (2 mL) was added triphosgene (59 mg, 0.20mmol) followed by DIEA (209 μL L1.20 mmol). The mixture was stirred for1 hour at ambient temperature then treated with(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation F; 145 mg, 0.44 mmol) and DIEA (209 μL, 1.20 mmol). Afterstirring at ambient temperature for 18 hours, the mixture waspartitioned between saturated NH₄Cl (20 mL) and DCM (20 mL) and theaqueous layer extracted with DCM (2×10 mL). The combined organic phaseswere washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica columnchromatography eluting with 3-4% MeOH/DCM to afford the title compound(99 mg, 47% yield) as a white solid. MS (apci) m/z=533.2 (M+H).

The following compounds were made according to Example 486, replacingethyl nicotinate with the appropriate reagent in Step A, and for Example490 also replacing phenylhydrazine hydrochloride with3-hydrazinylpyridine hydrochloride in Step B.

MS (apci) Ex. # Structure Name m/z 487

1-((3S,4R)-4-(3,4-difluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3- (pyridin-4-yl)-1H-pyrazol-5- yl)urea 533.2(M + H) 488

1-((3S,4R)-4-(3,4-difluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3- (pyridin-2-yl)-1H-pyrazol-5- yl)urea 533.2(M + H) 489

1-((3S,4R)-4-(3,4-difluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(5-fluoropyridin-3-yl)-4- methyl-1-phenyl-1H-pyrazol-5- yl)urea551.2 (M + H) 490

1-((3S,4R)-4-(3,4-difluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(5-fluoropyridin-3-yl)-4- methyl-1-(pyridin-3-yl)-1H-pyrazol-5-yl)urea 552.2 (M + H) 491

1-((3S,4R)-4-(3,4-difluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl- 1H,1′H-[3,3′-bipyrazol]-5-yl)urea 536.2(M + H)

Example 492

1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,3′-bipyrazol]-5-yl)-3-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the procedure of Example 491, replacing(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation F) with(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride (Preparation K) in Step C. Material was purified bysilica column chromatography eluting with 3% MeOH/DCM to afford thetitle compound (52 mg, 51% yield) as a pale yellow foam. MS (apci)m/z=518.2 (M+H).

Example 493

1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,3′-bipyrazol]-5-yl)urea

Prepared according to the procedure of Example 491, replacing(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation F) with(3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminetrifluoroacetate (Preparation E) in Step C. Material was purified bysilica column chromatography eluting with 3% MeOH/DCM to afford thetitle compound (33 mg, 31% yield) as a white solid. MS (apci) m/z=536.2(M+H).

Example 494

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2′,4-dimethyl-1-phenyl-1H,2′H-[3,3′-bipyrazol]-5-yl)ureaStep A: Preparation of2′,4-dimethyl-1-phenyl-1H,2′H-[3,3′-bipyrazol]-5-amine

Prepared according to the method of Example 486, Step A, replacing ethylnicotinate with ethyl 1-methyl-1H-pyrazole-5-carboxylate. ¹H NMR (CDCl₃)δ 7.55 (d, J=2.2 Hz, 1H), 7.01 (d, J=2.2 Hz, 1H), 4.19 (s, 3H), 4.12 (q,J=7.2 Hz, 1H), 1.65 (d, J=7.2 Hz, 3H) ppm.

Step B: Preparation of phenyl(2′,4-dimethyl-1-phenyl-1H,2′H-[3,3′-bipyrazol]-5-yl)carbamate

To a solution of 2′,4-dimethyl-1-phenyl-1H,2′H-[3,3′-bipyrazol]-5-amine(100 mg, 0.39 mmol) in EtOAc (2 mL) was added 2N NaOH (395 μL, 0.79mmol) followed by phenyl chloroformate (75 μL, 0.59 mmol). The mixturewas stirred at ambient temperature for 4 hours then treated with afurther aliquot of phenyl chloroformate (50 μL) and stirred for 18hours. The mixture was partitioned between water (20 mL) and EtOAc (10mL) and the aqueous layer extracted with EtOAc (2×10 mL). The combinedorganic phases were washed with saturated NaHCO₃ (10 mL) and brine (10mL) then dried over Na₂SO₄, filtered and concentrated in vacuo to affordphenyl (2′,4-dimethyl-1-phenyl-1H,2′H-[3,3′-bipyrazol]-5-yl)carbamate(140 mg, 95% yield) as a pale yellow gum. MS (apci) m/z=374.2 (M+H).

Step C: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2′,4-dimethyl-1-phenyl-1H,2′H-[3,3′-bipyrazol]-5-yl)urea

To a solution of(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation F; 68 mg, 0.21 mmol) and phenyl(2′,4-dimethyl-1-phenyl-1H,2′H-[3,3′-bipyrazol]-5-yl)carbamate (70 mg,0.19 mmol) in DCM (2 mL) was added DIEA (114 μL, 0.66 mmol). Afterstirring at ambient temperature for 3 hours the mixture was partitionedbetween saturated NH₄Cl (20 mL) and DCM (20 mL) and the aqueous layerextracted with DCM (2×10 mL). The combined organic phases were washedwith brine (10 mL) then dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by silica column chromatography elutingwith 1-3% MeOH/DCM to afford the title compound (68 mg, 68% yield) as awhite solid. MS (apci) m/z=536.2 (M+H).

Example 495

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-(5-fluoropyridin-3-yl)-1′,4-dimethyl-1H,1′H-[3,4′-bipyrazol]-5-yl)ureaStep A: Preparation of3-(2-(diphenylmethylene)hydrazinyl)-5-fluoropyridine

A solution of 3-bromo-5-fluoropyridine (5.0 g, 28.4 mmol),benzophenonehydrazone (6.13 g, 31.3 mmol) and Xantphos (164 mg, 0.28mmol) was degassed with N₂ for 10 minutes then treated with sodiumt-butoxide (3.82 g, 39.8 mmol) and palladium (II) acetate (64 mg, 0.28mmol). The heterogeneous mixture was stirred at 85° C. in a sealedvessel for 18 hours. The cooled mixture was partitioned between water(100 mL) and EtOAc (100 mL) and the aqueous layer extracted with EtOAc(2×50 mL). The combined organic phases were washed with brine (50 mL),dried over Na₂SO₄, filtered and concentrated in vacuo. The residue wastriturated with Et₂O, filtered and dried in vacuo to afford3-(2-(diphenylmethylene)hydrazinyl)-5-fluoropyridine (6.3 g, 72% yield)as a beige powder. MS (apci) m/z=292.1 (M+H).

Step B: Preparation of 1-(5-fluoropyridin-3-yl)-1′,4-dimethyl-1H,1′H-[3,4′-bipyrazol]-5-amine

A solution of 2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropanenitrile(Example 491, Step A; 100 mg, 0.61 mmol),3-(2-(diphenylmethylene)hydrazinyl)-5-fluoropyridine (162 mg, 0.56 mmol)and p-toluenesulfonic acid monohydrate (530 mg, 2.79 mmol) in EtOH (3mL) was stirred at 80° C. in a sealed vial for 18 hours. The cooledmixture was treated with saturated NaHCO₃ (30 mL) and extracted with DCM(3×10 mL). The combined organic phases were washed with brine (10 mL),dried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica column chromatography eluting with 1-3% MeOH/DCM toafford 1-(5-fluoropyridin-3-yl)-1′,4-dimethyl-1H,1′H-[3,4′-bipyrazol]-5-amine (71 mg, 47%) as a pale yellow solid. MS(apci) m/z=273.1 (M+H).

Step C: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-(5-fluoropyridin-3-yl)-1′,4-dimethyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea

To a solution of 1-(5-fluoropyridin-3-yl)-1′,4-dimethyl-1H,1′H-[3,4′-bipyrazol]-5-amine (35 mg, 0.13 mmol) in DCM (2 mL) was addedtriphosgene (19 mg, 0.06 mmol) followed by DIEA (67 μL, 0.39 mmol). Themixture was stirred for 1 hour at ambient temperature then treated with(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation F; 42 mg, 0.13 mmol) and DIEA (67 μL, 0.39 mmol) andstirring continued for 18 hours. The mixture was partitioned betweensaturated NH₄Cl (20 mL) and DCM (20 mL) and the aqueous layer extractedwith DCM (2×10 mL). The combined organic phases were washed with brine(10 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by silica column chromatography eluting with 2.5-4%MeOH/DCM to afford the title compound (33 mg, 46%) as a white solid. MS(apci) m/z=555.2 (M+H).

Example 496

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-(5-methylpyridin-3-yl)-1H,1′H-[3,4′-bipyrazol]-5-yl)urea

Prepared according to the procedure of Example 495, replacing3-bromo-5-fluoropyridine with 3-bromo-5-methylpyridine in Step A.Material was purified by silica column chromatography eluting with 5-10%MeOH/DCM to afford the title compound (41 mg, 56% yield) as a creamsolid. MS (apci) m/z=551.2 (M+H).

Example 497

1-(1-(5-chloropyridin-3-yl)-1′,4-dimethyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the procedure of Example 495, replacing3-bromo-5-fluoropyridine with 3-bromo-5-chloropyridine in Step A.Material was purified by silica column chromatography eluting with 2-5%MeOH/DCM to afford the title compound (85 mg, 86% yield) as a pale pinksolid. MS (apci) m/z=571.2 (M+).

Example 498

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-1′-(2,2,2-trifluoro-1-(2,2,2-trifluoroethoxy)ethyl)-1H,1′H-[3,4′-bipyrazol]-5-yl)urea Step A: Preparation of ethyl1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate

To a mixture of ethyl 1H-pyrazole-4-carboxylate (3 g, 21.4 mmol) andK₂CO₃ (3.55 g, 25.7 mmol) in DMF (10 mL) was added1-(chloromethyl)-4-methoxybenzene (3.50 mL, 25.7 mmol). The reaction wasstirred at ambient temperature for 18 hours then ether (30 mL) and water(10 mL) were added. The organic layer was separated, washed with brine,dried over Na₂SO₄ and concentrated in vacuo. The residue was purified bysilica column chromatography eluting with 3:1 hexanes/EtOAc to affordethyl 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (5.7 g, 102%) as acolorless oil. ¹H NMR (CDCl₃) δ 7.92 (m, 1H), 7.80 (m, 1H), 7.21 (m,2H), 6.89 (m, 2H), 5.23 (s, 2H), 4.27 (m, 2H), 3.80 (s, 3H), 1.32 (m,3H) ppm.

Step B: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′-(4-methoxybenzyl)-4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea

Prepared according to the procedure of Example 494, replacing ethyl1-methyl-1H-pyrazole-5-carboxylate with ethyl1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate in Step A. Material waspurified by silica column chromatography eluting with 1:1 to 1:1.2hexanes/acetone plus 0.5% NH₄OH to afford1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′-(4-methoxybenzyl)-4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea (800 mg, 60% yield) as a white solid. MS(apci) m/z=642.3 (M+H).

Step C: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)urea

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′-(4-methoxybenzyl)-4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea (241 mg, 0.38 mmol) was combined with TFA(2 mL) in a sealed tube and stirred at 70° C. for 18 hours. The cooledmixture was concentrated in vacuo and the residue partitioned between 1NNaOH (20 mL) and DCM (10 mL). The aqueous layer was extracted with DCM(2×10 mL) and the combined organic phases were washed with saturatedNaHCO₃ (10 mL) and brine (10 mL) then dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica columnchromatography eluting with 2-5% MeOH/DCM to afford1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea(144 mg, 74% yield) as a white solid. MS (apci) m/z=522.2 (M+).

Step D: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-′-(2,2,2-trifluoro-1-(2,2,2-trifluoro-ethoxy)ethyl)-1H,1,1′H-[3,4′-bipyrazol]-5-yl)urea

To a solution of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea(50 mg, 0.10 mmol) in DMF (2.5 mL) at −78° C. was added potassiumt-butoxide (264 μL, 1M/THF, 0.264 mmol). The mixture was stirred for 10minutes then treated with 2,2,2-trifluoroethyl trifluoromethanesulfonate(13.1 μL, 0.09 mmol). After stirring at ambient temperature for 2 hoursthe mixture was partitioned between saturated NH₄Cl (20 mL) and EtOAc(10 mL) and the aqueous layer extracted with EtOAc (2×10 mL). Thecombined organic phases were washed with water (2×10 mL) and brine (10mL) then dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by silica column chromatography eluting with 2.5%MeOH/DCM to afford the title compound (29 mg, 43% yield) as a colorlessglass. MS (apci) m/z=702.2 (M+H).

Example 499

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-1′-(2,2,2-trifluoroethyl)-1H,1′H-[3,4′-bipyrazol]-5-yl)urea

To a solution of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea(Example 498, Step C; 20 mg, 0.04 mmol) in DMF (0.5 mL) was added K₂CO₃(16 mg, 0.12 mmol) followed by trifluoroethyl triflate (6 μL, 0.04mmol). The mixture was sealed and stirred at ambient temperature for 5hours. A further aliquot of trifluoroethyl triflate (30 μL) was addedand stirring was continued for 18 hours. The mixture was partitionedbetween water (10 mL) and EtOAc (10 mL) and the aqueous layer extractedwith EtOAc (2×10 mL). The combined organic phases were washed with water(4×10 mL) and brine (10 mL) then dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica columnchromatography eluting with 2-5% MeOH/DCM to afford the title compound(8 mg, 35% yield) as a colorless glass. MS (apci) m/z=604.2 (M+H).

Example 500

1-(1′-(cyclopropylmethyl)-4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the procedure of Example 499, replacingtrifluoroethyl triflate with (bromomethyl)cyclopropane. Material waspurified by silica column chromatography eluting with 2.5-5% MeOH/DCM toafford the title compound (16 mg, 31% yield) as a white solid. MS (apci)m/z=576.3 (M+H).

Example 501

1-(1′-(cyclopropanecarbonyl)-4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

To a solution of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea(Example 498, Step C; 50 mg, 0.09 mmol) in DCM (2 mL) at 0° C. was addedcyclopropylcarbonyl chloride (13 μL, 0.14 mmol) followed by DIEA (67 μL,0.38 mmol). The mixture was allowed to warm slowly to ambienttemperature over 18 hours then partitioned between saturated NaHCO₃ (20mL) and DCM (10 mL) and the aqueous layer extracted with DCM (2×10 mL).The combined organic phases were washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica column chromatography eluting with 2.5% MeOH/DCM to afford thetitle compound (26 mg, 46% yield) as a white solid. MS (apci) m/z=590.2(M+H).

Example 502

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1′-(methylsulfonyl)-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)urea

Prepared according to the procedure of Example 501, replacingcyclopropyl carbonyl chloride with mesyl chloride. Material was purifiedby silica column chromatography eluting with 2-5% MeOH/DCM to afford thetitle compound (39 mg, 68% yield) as a colorless glass. MS (apci)m/z=600.2 (M+H).

Example 503

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′-isopropyl-4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)ureaStep A: Preparation of 3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-amine

To a suspension of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one(Intermediate P135, Step A; 1.60 g, 8.46 mmol) in acetonitrile (30 mL)was added phosphorus oxybromide (3.64 g, 12.7 mmol) in one portion. Themixture was stirred at reflux for 3 hours then cooled and concentratedin vacuo. The residue was treated with DCM (50 mL) then saturated NaHCO₃(50 mL) was slowly added. The mixture was stirred for 30 minutes thenthe layers separated and the aqueous layer extracted with DCM (2×50 mL).The combined organic phases were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica column chromatography eluting with 2:1 hexanes/EtOAc, to afford3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-amine (273 mg, 13% yield) as awhite solid. MS (apci) m/z=254.0 (M+H).

Step B: Preparation of phenyl(3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate

To a solution of 3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-amine (339 mg,1.34 mmol) in EtOAc (10 mL) was added 2N NaOH (2 mL, 4.0 mmol) followedby phenyl chloroformate (337 μL, 2.69 mmol). The mixture was stirred atambient temperature for 5 hours then partitioned between water (30 mL)and EtOAc (30 mL) and the aqueous layer extracted with EtOAc (2×20 mL).The combined organic phases were washed with saturated NaHCO₃ (30 mL)and brine (30 mL) then dried over Na₂SO₄, filtered and concentrated invacuo to afford phenyl(3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate which was useddirectly assuming quantitative yield. MS (apci) m/z=374.0 (M+H).

Step C: Preparation of1-(3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

To a solution of(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation F; 464 mg, 1.41 mmol) and phenyl(3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate (500 mg, 1.34 mmol)in DCM (10 mL) was added DIEA (819 μL, 4.7 mmol). The solution wasstirred at ambient temperature for 18 hours then partitioned betweensaturated NH₄Cl (30 mL) and DCM (30 mL) and the aqueous layer extractedwith DCM (2×20 mL). The combined organic phases were washed with brine(20 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by silica column chromatography eluting with 2%MeOH/DCM to afford1-(3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea(483 mg, 67% yield) as a white solid. MS (apci) m/z=534.1 (M+).

Step D: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′-isopropyl-4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea

1-(3-Bromo-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea (30 mg, 0.06 mmol),1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(20 mg, 0.08 mmol), tricyclohexyl phospine (3 mg, 0.01 mmol) andPd₂(dba)₃ (5 mg, 0.006 mmol) were combined in a sealed tube and1,4-dioxanes (561 μL) were added. The solution was purged with N₂ for 30seconds then treated with K₃PO₄ (130 μL, 1.3 M, 0.17 mmol), sealed andstirred at 100° C. for 1 hour. The cooled mixture was concentrated invacuo and the residue purified by silica column chromatography elutingwith 2.5-10% MeOH/DCM to afford the title compound (12 mg, 38% yield) asa colorless glass. MS (apci) m/z=564.2 (M+H).

The following compounds were made according to the method of Example503, replacing1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewith the appropriate reagent in Step D.

MS (apci) Ex. # Structure Name m/z 504

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (4-methyl-1-phenyl-3-(pyrimidin-5-yl)-1H-pyrazol-5- yl)urea 534.2 (M + H) 505

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (4-methyl-3-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-1- phenyl-1H-pyrazol-5-yl)urea 563.3 (M + H)506

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1- phenyl-1H-pyrazol-5-yl)urea 563.3 (M + H)507

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (1′,4,5′-trimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea 550.2 (M + H) 508

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (1′,3′,4-trimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea 550.2 (M + H) 509

1-(1′-cyclopropyl-4-methyl-1- phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea 562.2 (M + H) 510

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3- (4-methyl-3-(2-methylthiazol-5-yl)-1-phenyl-1H-pyrazol-5- yl)urea 553.2 (M + H) 511

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5- yl)urea 548.2 (M + H) 512

1-(3-(2-aminopyrimidin-5-yl)-4- methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)urea 549.2 (M + H) 513

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (3-(2,4-dimethylthiazol-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5- yl)urea 567.2 (M + H) 514

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (3-(2,6-dimethylpyridin-4-yl)-4-methyl-1-phenyl-1H-pyrazol-5- yl)urea 561.3 (M + H) 515

1-(3-(6-aminopyridin-3-yl)-4- methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)urea 548.2 (M + H)

Example 516

1-(3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the procedure of Example 503, Step C, replacing(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation F) with(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride (Preparation K). Material was purified by silica columnchromatography eluting with 2-3% MeOH/DCM to afford the title compound(526 mg, 63%) as a cream solid. MS (apci) m/z=518.1 (M+H).

Example 517

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the procedure of Example 503, replacing1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewith5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)pyridin-2(1H)onein Step D. Material was purified by silica column chromatography elutingwith 2% MeOH/DCM followed by reverse phase HPLC purification (5-95%ACN/water/0.5% TFA over 20 minutes). The title compound (5.5 mg, 9%yield) was obtained after aqueous work-up (1N NaOH/DCM) as a whitesolid. MS (apci) m/z=631.2 (M+H).

Example 518

1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′-isopropyl-4-methyl-1-phenyl-1H,1′H-r[3,4′-bipyrazol]-5-yl)urea

Prepared according to the procedure of Example 503, replacing(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation F) with(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride (Preparation K) in Step C. Material was purified bysilica column chromatography eluting with 2-3% MeOH/DCM followed byreverse phase HPLC purification (5-95% ACN/water/0.5% TFA over 20minutes). The title compound (37 mg, 18% yield) was obtained afteraqueous work-up (1N NaOH/DCM) as a colorless gum. MS (apci) m/z=546.3(M+H).

Example 519

1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the procedure of Example 518, replacing1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewith1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-onein Step D. Material was purified by silica column chromatography elutingwith 2-5% MeOH/DCM to afford the title product (29 mg, 27% yield) as awhite solid. MS (apci) m/z=545.2 (M+H).

Example 520

1-(3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea

Prepared according to the procedure of Example 516, replacing(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride (Preparation K) with(3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-aminehydrochloride (Example 265, Step A). Material was purified by silicacolumn chromatography eluting with 2:1 hexanes/EtOAc to afford the titlecompound (173 mg, 62% yield) as a white solid. MS (apci) m/z=522.1 (M+).

Example 521

1-(4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea

Prepared according to the procedure of Example 519, replacing(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride (Preparation K) with(3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-aminehydrochloride (Example 265, Step A) in Step C. Material was purified bysilica column chromatography eluting with 2% MeOH/DCM to afford thetitle product (28 mg, 33% yield) as a pale yellow solid. MS (apci)m/z=550.2 (M+).

Example 522

1-(3-(2-aminopyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)ureabis(2,2,2-trifluoroacetate

Prepared according to the procedure of Example 512, replacing(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride (Preparation K) with(3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-aminehydrochloride (Example 265, Step A) in Step C. Material was purified bysilica column chromatography eluting with 2-5% MeOH/DCM followed byreverse phase HPLC purification (5-95% ACN/water/0.5% TFA over 20minutes). The title compound (3 mg, 3% yield) was obtained as a whitesolid as a di-TFA salt. MS (apci) m/z=537.2 (M+H).

Example 523

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′-ethyl-4-methyl-1-phenyl-1H,1′H-r[3,4′-bipyrazol]-5-yl)ureaStep A: Preparation of 1′-ethyl-4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-amine

3-Bromo-4-methyl-1-phenyl-1H-pyrazol-5-amine (Example 503, Step A; 100mg, 0.39 mmol),1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (176mg, 0.79 mmol), K₂CO₃ (219 mg, 1.59 mmol) and Pd(PPh₃)₄(46 mg, 0.039mmol) were combined in toluene (2 mL), water (1 mL) and EtOH (0.5 mL)and stirred at 95° C. in a sealed tube for 18 hours. The cooled mixturewas filtered through GF paper and the filtrate partitioned between water(10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc(2×10 mL) and the combined organic phases were washed with brine (10mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by silica column chromatography eluting with 1.5% MeOH/DCMto afford 1′-ethyl-4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-amine (78mg, 74% yield) as a colorless gum. MS (apci) m/z=268.1 (M+H).

Step B: Preparation of phenyl (1′-ethyl-4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)carbamate

To a solution of 1′-ethyl-4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-amine (78 mg, 0.29 mmol) in EtOAc (5 mL) wasadded 2N NaOH (0.44 mL, 0.87 mmol) followed by phenyl chloroformate (73μL, 0.58 mmol). The mixture was stirred at ambient temperature for 18hours then partitioned between water (20 mL) and EtOAc (20 mL) and theaqueous layer extracted with EtOAc (2×10 mL). The combined organicphases were washed with saturated NaHCO₃ (10 mL) and brine (10 mL) thendried over Na₂SO₄, filtered and concentrated in vacuo to afford phenyl(1′-ethyl-4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)carbamate as apale yellow oil. Used directly assuming quantitative yield. MS (apci)m/z=388.2 (M+H).

Step C: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′-ethyl-4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea

To a solution of(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation F; 56 mg, 0.17 mmol) and phenyl(1′-ethyl-4-methyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)carbamate (66mg, 0.17 mmol) in DCM (2 mL) was added DIEA (150 μL, 0.85 mmol). Afterstirring at ambient temperature for 18 hours the mixture was partitionedbetween saturated NH₄Cl (10 mL) and DCM (10 mL) and the aqueous layerextracted with DCM (2×10 mL). The combined organic phases were washedwith brine (10 mL) then dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by silica column chromatography elutingwith 2.5-3.5% MeOH/DCM to afford the title compound (35 mg, 37% yield)as a colorless glass. MS (apci) m/z=550.2 (M+H).

Example 524

1-(1′-ethyl-4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the procedure of Example 523, replacing(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation F) with(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride (Preparation K) in Step C. Material was purified bysilica column chromatography eluting with 3% MeOH/DCM to afford thetitle product (29 mg, 30% yield) as a white solid. MS (apci) m/z=532.3(M+H).

Example 525

5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yltrifluoromethanesulfonate Step A: Preparation of5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl trifluoromethane sulfonate

A suspension of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one(Intermediate P135, Step A; 0.50 g, 2.64 mmol) andN-phenylbis(trifluoromethylsulfonamide) (0.99 g, 2.77 mmol) in DMF (5mL) was treated with DIEA (1.38 mL, 7.93 mmol) and the mixture stirredat ambient temperature for 64 hours. The mixture was partitioned betweensaturated NaHCO₃ (30 mL) and EtOAc (30 mL) and the aqueous layer wasextracted with EtOAc (2×20 mL). The combined organic phases were washedwith water (5×10 mL) and brine (10 mL) then dried over Na₂SO₄, filteredand concentrated in vacuo. The residue was purified by silica columnchromatography eluting with 2:1 hexanes/EtOAc, to afford5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl trifluoromethane sulfonate(817 mg, 92% yield) as a pale yellow oil. MS (apci) m/z=322.0 (M+H).

Step B: Preparation of4-methyl-5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yltrifluoromethanesulfonate

Prepared according to the procedure of Example 503, Step B, replacing3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-amine with5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl trifluoromethane sulfonate. MS(apci) m/z=442.0 (M+H).

Step C: Preparation of5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yltrifluoromethanesulfonate

Prepared according to the procedure for Example 503, Step C, replacingphenyl (3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate with4-methyl-5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yltrifluoromethanesulfonate. Material was purified by silica columnchromatography eluting with 1.5-4% MeOH/DCM to afford the title compound(191 mg, 62% yield) as a white solid. MS (apci) m/z=604.2 (M+H).

Example 526

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureaStep A: Preparation of3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-amine

5-Amino-4-methyl-1-phenyl-1H-pyrazol-3-yl trifluoromethane sulfonate(Example 525, Step A; 200 mg, 0.62 mmol), 2-methoxypyrimidin-5-ylboronicacid (192 mg, 1.25 mmol), K₂CO₃ (344 mg, 2.49 mmol) and Pd(PPh₃)₄(72 mg,0.06 mmol) were combined in toluene (2 mL), water (1 mL) and EtOH (0.5mL) and stirred at 95° C. in a sealed tube for 18 hours. The cooledmixture was filtered through GF paper and the filtrate partitionedbetween water (20 mL) and EtOAc (20 mL). The aqueous layer was extractedwith EtOAc (2×20 mL) and the combined organic phases were washed withbrine (20 mL), dried over Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by silica column chromatography eluting with 1%MeOH/DCM to afford3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-amine (138mg, 79% yield) as a cream foam. MS (apci) m/z=282.1 (M+H).

Step B: Preparation of phenyl(3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate

Prepared according to the procedure of Example 503, Step B, replacing3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-amine with3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-amine.Material was purified by silica column chromatography eluting with 1%MeOH/DCM to afford phenyl(3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate(92 mg, 47% yield) as a cream foam. MS (apci) m/z=402.1 (M+H).

Step C: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the procedure of Example 503, Step C, replacingphenyl (3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate with phenyl(3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate.Material was purified by silica column chromatography eluting with 2.5%MeOH/DCM to afford the title compound (31 mg, 48% yield) as a whitesolid. MS (apci) m/z=564.2 (M+H).

Example 527

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-(dimethylamino)pyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the procedure of Example 526, replacing2-methoxypyrimidin-5-ylboronic acid withN,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)pyrimidin-2-aminein Step A. Material was purified by silica column chromatography elutingwith 3% MeOH/DCM to afford the title compound (22 mg, 32% yield) as awhite solid. MS (apci) m/z=577.3 (M+H).

Example 528

1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the procedure of Example 526, replacing(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation F) with(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(2S,3S)-2,3-bis((4-methylbenzoyl) oxy) succinate (Preparation L1, StepsA-D) in Step C. Material was purified by silica column chromatographyeluting with 3% MeOH/DCM to afford the title compound (32 mg, 51% yield)as a white solid. MS (apci) m/z=546.2 (M+H).

Example 529

1-(3-(2-(dimethylamino)pyrimidin-5-yl)-4-methyl-1-phenyl-H-pyrazol-5-yl)-3-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the procedure of Example 527, replacing(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation F) with(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride (Preparation K) in Step C. Material was purified bysilica column chromatography eluting with 3% MeOH/DCM to afford thetitle compound (27 mg, 40% yield) as a white solid. MS (apci) m/z=559.3(M+H).

Example 530

1-(1′-ethyl-4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-vyl)-3-((3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the procedure of Example 526, replacing2-methoxypyrimidin-5-ylboronic acid with1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inStep A, and(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation F) with(3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride (Preparation L11) in Step C. Material was purified bysilica column chromatography eluting with 3% MeOH/DCM to afford thetitle compound (39 mg, 57% yield) as a white solid. MS (apci) m/z=532.3(M+H).

Example 531

1-((3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the procedure of Example 526, replacing2-methoxypyrimidin-5-ylboronic acid with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-onein Step A, and(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation F) with(3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride (Preparation L1) in Step C. Material was purified bysilica column chromatography eluting with 3-8% MeOH/DCM to afford thetitle compound (38 mg, 54% yield) as a white solid. MS (apci) m/z=545.2(M+H).

Example 532

1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the procedure of Example 526, replacing2-methoxypyrimidin-5-ylboronic acid with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-onein Step A, and(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation F) with(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(2S,3S)-2,3-bis((4-methylbenzoyl)oxy) succinate (Preparation L1, StepsA-D) in Step C. Material was purified by silica column chromatographyeluting with 3-8% MeOH/DCM to afford the title compound (34 mg, 49%yield) as a white solid. MS (apci) m/z=545.3 (M+H).

Example 533

1-(3-cyclopropyl-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureaStep A: Preparation of3-cyclopropyl-4-methyl-1-phenyl-1H-pyrazol-5-amine

A suspension of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yltrifluoromethane sulfonate (Example 525, Step A; 200 mg, 0.62 mmol) intoluene:water, 10:1 (5.5 mL) in a sealed tube was degassed with Argonfor 5 minutes. Potassium cyclopropyltrifluoroborate (368 mg, 2.49 mmol),Pd(OAc)₂ (21 mg, 0.09 mmol) and K₃PO₄ (396 mg, 1.87 mmol) were thenadded, followed by dicyclohexyl(2′,6′-diisopropylbiphenyl-2-yl)phosphine(87 mg, 0.19 mmol). The mixture was degassed with Argon for another 5minutes then sealed and stirred at 110° C. for 18 hours. The cooledmixture was diluted with water (30 mL) and extracted with EtOAc (3×20mL). The combined organic phases were washed with brine (20 mL), driedover Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica column chromatography eluting with 1% MeOH/DCM toafford 3-cyclopropyl-4-methyl-1-phenyl-1H-pyrazol-5-amine (100 mg, 75%yield) as a yellow oil. MS (apci) m/z=214.1 (M+H).

Step B: Preparation of1-(3-cyclopropyl-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the procedure of Example 526, Steps B and C,replacing3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-amine with3-cyclopropyl-4-methyl-1-phenyl-1H-pyrazol-5-amine in Step B. Materialwas purified by silica column chromatography eluting with 1-3% MeOH/DCMto afford the title product (29 mg, 39% yield) as a colorless glass. MS(apci) m/z=496.3 (M+H).

Example 534

1-(3-cyclopropyl-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the procedure of Example 533, replacing(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation F) with(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (2S,3S)-2,3-bis((4-methylbenzoyl)oxy) succinate (Preparation L1, StepsA-D) in Step C. Material was purified by silica column chromatographyeluting with 2-4% MeOH/DCM to afford the title compound (11 mg, 15%yield) as a colorless glass. MS (apci) m/z=478.3 (M+H).

Example 535

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureaStep A: Preparation of1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

5-Bromo-1-isopropylpyridin-2(1H)-one (500 mg, 2.31 mmol),bis(pinnacolato) diboron (881 mg, 3.47 mmol) and potassium acetate (681mg, 6.94 mmol) were combined in a sealed vessel in 1,4-dioxanes (5 mL)and purged with Argon for 5 minutes. PdCl₂(dppf)dcm (189 mg, 0.23 mmol)was then added, purging continued for 1 minute, then the vessel sealedand heated at 100° C. for 18 hours. The cooled mixture was filteredthrough GF paper and rinsed with EtOAc and DCM. The filtrate wasconcentrated in vacuo and the residue purified by silica columnchromatography eluting with 1% MeOH/DCM, followed by a second columneluting with 1:1 hexanes/EtOAc. The resulting solid was triturated withEt₂O, filtered and the filtrate concentrated in vacuo to afford1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(308 mg, 51% yield) as a peach solid. MS (apci) m/z=264.2 (M+H).

Step B: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the procedure of Example 526, replacing2-methoxypyrimidin-5-ylboronic acid with1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one.Material was purified by silica column chromatography eluting with2.5-4% MeOH/DCM to afford the title compound (37 mg, 53% yield) as acolorless glass. MS (apci) m/z=591.3 (M+H).

Example 536

1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the procedure of Example 535, replacing(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation F) with(3S,4R)-4-(4-fluoro-phenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(2S,3S)-2,3-bis((4-methylbenzoyl)oxy) succinate (Preparation L1, StepsA-D) in the final step. Material was purified by silica columnchromatography eluting with 3-5% MeOH/DCM to afford the title compound(34 mg, 50% yield) as a colorless glass. MS (apci) m/z=573.3 (M+H).

Example 537

1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((S)-2-hydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureadihydrochloride Step A: Preparation of1-(3-((S)-2-((tert-butyldimethylsilyl)oxy)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the method described for Example 1 usingIntermediate P211 as a replacement for3-tert-butyl-1-phenyl-1H-pyrazol-5-amine in Step A, and substituting(3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride for trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-aminedihydrochloride (Preparation B) in Step B. MS (apci) m/z=644.4 (M+H).

Step B: Preparation of1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((S)-2-hydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea dihy-drochloride

Prepared according to the procedure described for Example 179, using1-(3-((S)-2-((tert-butyldimethylsilyl)oxy)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureaas a replacement for 1-(3-((S)-2-((tert-butyldimethylsilyl)oxy)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluoro-phenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea(Preparation U-2). MS (apci) m/z=530.3 (M+H).

Example 538

1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(2-(piperazin-1-yl)ethoxy)-1H-pyrazol-5-yl)ureatrihydrochloride

To a stirred solution of tert-butyl4-(2-((5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yl)oxy)ethyl)piperazine-1-carboxylate (Example 388, 52 mg, 0.076 mmol) in DCM (3 mL)was added 2 N HCl in ether (0.15 mL). After stirring at ambienttemperature for 1 hour, the solvents were evaporated under reducedpressure to give the title compound (50 mg, 110% yield). MS (apci)m/z=584.3 (M+H).

Example 539

1-(3-(benzyloxy)-4-chloro-1-methyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the method described for Intermediate 201, Step B,using1-(3-(benzyloxy)-1-methyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea(Example 136) as a replacement for phenyl3-ethoxy-1-phenyl-1H-pyrazol-5-ylcarbamate. MS (apci) m/z=520.2 (M+H).

Example 540

2-((5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yl)oxy)aceticacid

A mixture of ethyl2-((5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yl)oxy)acetate(Example 361, 190 mg, 0.341 mmol) and 1.0 N aqueous LiOH solution (0.682mL, 0.682 mmol) in THF (4 mL) and MeOH (2 mL) was stirred at ambienttemperature for 1 hour. The reaction mixture was diluted with water. 1.0N HCl aqueous solution (0.8 mL) was added dropwise to adjust the pH to4. The mixture was extracted with EtOAc. The combined extracts werewashed with brine, dried over MgSO₄, filtered, and concentrated to givethe title compound as an off white solid (150 mg, 83% yield). MS (apci)m/z=530.2 (M+H).

Example 541

2-((5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yl)oxy)-N-ethylacetamide

To a stirred solution of2-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yloxy)aceticacid (Example 540, 22 mg, 0.042 mmol) in DMF (2 mL) was added EDCI (24mg, 0.12 mmol) and HOBt (17 mg, 0.12 mmol). The resulting mixture wasstirred at ambient temperature for 10 minutes. Ethylamine (2.0 M in THF,0.062 mL, 0.12 mmol) was added followed by TEA (0.017 mL, 0.12 mmol).The reaction mixture was stirred at ambient temperature for 3 days. Themixture was diluted with EtOAc, washed sequentially with saturatedaqueous NH₄Cl solution, saturated aqueous NaHCO₃ solution, and brine,dried over MgSO₄, and concentrated. The residue was purified by flashchromatography on silica gel (5% MeOH in DCM) to give the title compound(16 mg, 69% yield). MS (apci) m/z=557.3 (M+H).

Example 542

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-ethyl-3-(2-hydroxy-2-methylpropoxy)-1-phenyl-1H-pyrazol-5-yl)ureaStep A: Preparation of 5-amino-4-ethyl-1-phenyl-1H-pyrazol-3 (2H)-one

A mixture of ethyl 2-cyanobutanoate (10.0 g, 70.8 mmol), phenylhydrazine(7.66 g, 70.8 mmol), dioxane (20 mL), EtOH (50 mL) and NaOEt (3.0 M inEtOH, 2.36 mL, 7.08 mmol) was heated at 90° C. for 7 days. Aftercooling, the reaction mixture was concentrated. The residue was treatedwith Et₂O. The solid was collected by filtration, washed with Et₂O, anddried in vacuum to give the title compound (7.50 g, 52% yield). MS(apci) m/z=204.1 (M+H).

Step B: Preparation of1-((5-amino-4-ethyl-1-phenyl-1H-pyrazol-3-yl)oxy)-2-methylpropan-2-ol

Prepared according to the procedure described for Intermediate 203,using 5-amino-4-ethyl-1-phenyl-1H-pyrazol-3(2H)-one as a replacement for5-amino-1-phenyl-1H-pyrazol-3(2H)-one. MS (apci) m/z=276.2 (M+H).

Step C: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-ethyl-3-(2-hydroxy-2-methylpropoxy)-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the procedure described for Example 1 using1-((5-amino-4-ethyl-1-phenyl-1H-pyrazol-3-yl)oxy)-2-methylpropan-2-ol asa replacement for 3-tert-butyl-1-phenyl-1H-pyrazol-5-amine in Step A,and substituting(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride for trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-aminedihydrochloride (Preparation B) in Step B. MS (apci) m/z=558.3 (M+H).

Example 543

1-(3-(2-aminoethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

To a solution of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea(Example 387, 170 mg, 0.264 mmol) in 1:1 MeOH:THF (10 mL) at ambienttemperature was added hydrazine monohydrate (132 mg, 2.64 mmol). Thereaction was heated at 50° C. for 17 hours. After cooling, the mixturewas concentrated. The residue was triturated with DCM and the solid wasremoved by filtration. The filtrate was concentrated to give the titlecompound (106 mg, 78% yield). MS (apci) m/z=515.3 (M+H).

Example 544

N-(2-((5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yl)oxy)ethyl)methanesulfonamide

A mixture of1-(3-(2-aminoethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea(Example 543, 30 mg, 0.058 mmol), methanesulfonyl chloride (7.3 mg,0.064 mmol) and TEA (0.016 mL, 0.12 mmol) in DCM (3 mL) was stirred atambient temperature for 1 hour. The reaction mixture was diluted withEtOAc, washed with water and brine, dried over MgSO₄ and concentrated.The residue was purified by flash chromatography on silica gel (3% MeOHin DCM) to give the title compound (25 mg, 72% yield). MS (apci)m/z=593.2 (M+H).

Example 545

N-(2-((5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yl)oxy)ethyl)acetamide

Prepared according to the procedure described for Example 544, usingacetic anhydride as a replacement for methanesulfonyl chloride. MS(apci) m/z=557.3 (M+H).

Example 546

1-(3-(2-(4-acetylpiperazin-1-yl)ethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the procedure described for Example 544, usingacetic anhydride as a replacement for methanesulfonyl chloride, andsubstituting1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(2-(piperazin-1-yl)ethoxy)-1H-pyrazol-5-yl)ureatrihydrochloride (Example 538) for1-(3-(2-aminoethoxy)-4-methyl-1-phenyl-H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea(Example 543). MS (apci) m/z=626.4 (M+H).

Example 547

2-((5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-H-pyrazol-3-yl)oxy)acetamide

Prepared according to the procedure described for Example 544, usingammonium chloride as a replacement for ethylamine. MS (apci) m/z=529.2(M+H).

Example 548

N-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-3-ethoxy-1-phenyl-1H-pyrazol-4-yl)-2,2,2-trifluoroacetamideStep A: Preparation of benzyl(5-amino-3-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-4-yl)carbamate

Prepared according to the method described for Example 542, Step A,using ethyl 2-(benzyloxycarbonylamino)-2-cyanoacetate as a replacementfor ethyl 2-cyanobutanoate. MS (apci) m/z=325.1 (M+H).

Step B: Preparation of benzyl(5-amino-3-ethoxy-1-phenyl-1H-pyrazol-4-yl)carbamate

Prepared according to the method described for Intermediate P135, StepB, using benzyl(5-amino-3-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-4-yl)carbamate as areplacement for 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one. MS(apci) m/z=353.1 (M+H).

Step C: Preparation of benzyl(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-3-ethoxy-1-phenyl-1H-pyrazol-4-yl)carbamate

Prepared according to the procedure described for Example 151, Step Busing benzyl (5-amino-3-ethoxy-1-phenyl-1H-pyrazol-4-yl)carbamate as areplacement for2-(pyridin-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine, andsubstituting (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride for(3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-aminebis(2,2,2-trifluoroacetate) (Preparation D). MS (apci) m/z=635.3 (M+H).

Step D: Preparation ofN-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-3-ethoxy-1-phenyl-1H-pyrazol-4-yl)-2,2,2-trifluoro-acetamide

A solution of benzyl(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-3-ethoxy-1-phenyl-1H-pyrazol-4-yl)carbamate(75 mg, 0.12 mmol) in TFA (1 mL) was heated at 60° C. for 17 hours. Thereaction mixture was concentrated under reduced pressure. 5% EtOH intoluene was added to the residue and the mixture was concentrated againto afford the crude product as a TFA salt. The crude material was takenup in EtOAc, washed with saturated aqueous NaHCO₃ solution and brine,dried over MgSO₄, and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel (2% MeOH in DCM) togive the title compound (9 mg, 13% yield) as a minor product. MS (apci)m/z=597.2 (M+H).

Example 549

1-(4-amino-3-ethoxy-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the procedure described for Example 548, Step C.The title compound was isolated as a major product by columnchromatography on silica gel (5% MeOH in DCM). MS (apci) m/z=501.2(M+H).

Example 550

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-(2-hydroxyethyl)-1-phenyl-1H-pyrazol-5-yl)ureaStep A: Preparation of5-amino-4-(2,2-diethoxyethyl)-1-phenyl-1H-pyrazol-3(2H)-one

Prepared according to the method described for Example 542, Step A usingethyl 2-cyano-4,4-diethoxybutanoate as a replacement for ethyl2-cyanobutanoate. MS (apci) m/z=292.1 (M+H).

Step B: Preparation of4-(2,2-diethoxyethyl)-3-ethoxy-1-phenyl-1H-pyrazol-5-amine

Prepared according to the method described for Intermediate P135, StepB, using 5-amino-4-(2,2-diethoxyethyl)-1-phenyl-1H-pyrazol-3 (2H)-one asa replacement for 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one. MS(apci) m/z=320.2 (M+H).

Step C: Preparation of1-(4-(2,2-diethoxyethyl)-3-ethoxy-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the procedure described for Example 1 using4-(2,2-diethoxyethyl)-3-ethoxy-1-phenyl-1H-pyrazol-5-amine as areplacement for 3-tert-butyl-1-phenyl-1H-pyrazol-5-amine in Step A, andsubstituting(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride for trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-aminedihydrochloride (Preparation B) in step B. MS (apci) m/z=602.3 (M+H).

Step D: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-(2-oxoethyl)-1-phenyl-1H-pyrazol-5-yl)urea

A mixture of1-(4-(2,2-diethoxyethyl)-3-ethoxy-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea(0.13 g, 0.22 mmol), acetic acid (1 mL) and water (0.2 mL) was stirredat ambient temperature for 17 hours. The reaction was not complete byHPLC. Two drops of 30 wt. % HBr in AcOH solution was added. The reactionmixture was stirred for additional 17 hours. The reaction was quenchedby the addition of saturated aqueous NaHCO₃ solution, extracted withEtOAc, washed with saturated aqueous NaHCO₃ (2×) and brine, dried overMgSO₄, and concentrated to give the title compound which was used innext step without further purification. MS (apci) m/z=528.2 (M+H).

Step E: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-(2-hydroxyethyl)-1-phenyl-1H-pyrazol-5-yl)urea

To a stirred solution of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-(2-oxoethyl)-1-phenyl-1H-pyrazol-5-yl)urea(40 mg, 0.076 mmol) in THF (1 mL) was added dropwise a 2.0 M solution ofLiBH₄ in THF (0.038 mL, 0.076 mmol) at 0° C. The reaction was allowed towarm to ambient temperature and stirred for 3 hours. The reaction wasdiluted with EtOAc, washed with 0.1 N HCl, saturated aqueous NaHCO₃solution and brine, dried over MgSO₄, and concentrated. The residue waspurified by flash chromatography on silica gel (4% MeOH in DCM) to givethe title compound (4 mg, 10% yield). MS (apci) m/z=530.3 (M+H).

Example 551

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-(4-methylpiperazin-1-yl)ethoxy)-1-phenyl-1H-pyrazol-5-yl)ureatrihydrochloride

To a mixture of1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(2-(piperazin-1-yl)ethoxy)-1H-pyrazol-5-yl)ureatrihydrochloride (Example 538, 50 mg, 0.086 mmol), NaBH(OAc)₃ (73 mg,0.34 mmol) and THF (2 mL) was added formaldehyde (37% aqueous solution,14 mg, 0.17 mmol) at 0° C. The reaction mixture was warmed to ambienttemperature and stirred for 17 hours. The mixture was diluted with H₂O(20 mL) and extracted with DCM. The combined organic layers were driedover MgSO₄ and concentrated. The residue was purified by flashchromatography on silica gel (3% 7 N ammonia-MeOH in DCM) to give thefree base, which was treated with 2 N HCl in ether (3 drops). Themixture was concentrated and triturated with Et₂O to give the titlecompound (22 mg, 43% yield). MS (apci) m/z=598.3 (M+H).

Example 552

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-morpholino-2-oxoethoxy)-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the procedure described for Example 541, usingmorpholine as a replacement for ethylamine. MS (apci) m/z=599.3 (M+H).

Example 553

4-bromo-5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazole-3-carboxylicacid

Prepared according to the procedure described for Example 540, usingethyl4-bromo-5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazole-3-carboxylate(Example 381) as a replacement for ethyl2-((5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yl)oxy)acetate(Example 361). MS (apci) m/z=564.2 (M+H).

Example 554

4-bromo-5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-N-methyl-1-phenyl-1H-pyrazole-3-carboxamide

Prepared according to the procedure described for Example 541 using4-bromo-5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazole-3-carboxylicacid (Example 553) as a replacement for2-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yloxy)aceticacid (Example 540), and substituting methylamine for ethylamine. MS(apci) m/z=577.1 (M+H).

Example 555

4-bromo-5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-N-methoxy-1-phenyl-1H-pyrazole-3-carboxamide

Prepared according to the procedure described for Example 541, using4-bromo-5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazole-3-carboxylicacid (Example 553) as a replacement for2-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yloxy)aceticacid (Example 540), and substituting O-methylhydroxylamine hydrochloridefor ethylamine. MS (apci) m/z=593.1 (M+H).

Example 556

1-(4-chloro-1′-(2-methoxyethyl)-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureaStep A: Preparation of ethyl1-(2-methoxyethyl)-1H-pyrazole-4-carboxylate

A mixture of ethyl 1H-pyrazole-4-carboxylate (5.00 g, 35.7 mmol), DMF(120 mL), K₂CO₃ (19.7 g, 143 mmol) and 1-bromo-2-methoxyethane (9.92 g,71.4 mmol) was stirred at 80° C. for 4 hours. After cooling, thereaction mixture was poured into water and extracted with EtOAc. Thecombined extracts were washed with water and brine, dried andconcentrated. The residue was purified by column chromatography (4:1hexanes/EtOAc) to give the title compound (5.57 g, 79% yield) as acolorless oil. MS (apci) m/z=199.1 (M+H).

Step B: Preparation of 1′-(2-methoxyethyl)-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-amine

Prepared according to the method described for Intermediate P109,replacing methyl 2-methoxyacetate with ethyl1-(2-methoxyethyl)-1H-pyrazole-4-carboxylate in Step A. MS (apci)m/z=284.1 (M+H).

Step C: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′-(2-methoxyethyl)-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)urea

Prepared according to the procedure described for Example 1 using1′-(2-methoxyethyl)-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-amine as areplacement for 3-tert-butyl-1-phenyl-1H-pyrazol-5-amine in Step A, andsubstituting(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride for trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-aminedihydrochloride (Preparation B) in Step B. MS (apci) m/z=566.2 (M+H).

Step D: Preparation of 1-(4-chloro-1′-(2-methoxyethyl)-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

To a solution of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′-(2-methoxyethyl)-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)urea(40 mg, 0.071 mmol) in DCM (1 mL) was added N-chlorosuccinimide (11 mg,0.085 mmol) followed by catalytic amount of pyridinium4-methylbenzenesulfonate (PPTS). The mixture was stirred at ambienttemperature overnight. Additional N-chlorosuccinimide (4 mg) was added.The reaction was stirred at ambient temperature for 4 additional hours.The reaction mixture was partitioned between DCM and saturated aqueousNaHCO₃ solution. The aqueous layer was extracted with DCM. The combinedorganic layers were washed with brine, dried and concentrated. Theresidue was purified by reverse phase preparative HPLC (5-95%acetonitrile in water) to give the title compound (15 mg, 35% yield) asa white solid. MS (apci) m/z=600.2 (M+H).

Example 557

1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((S)-2,3-dihydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared from 1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea(Example 392; 38.0 mg, 0.065 mmol) according to the procedure describedfor Example 176, to provide title compound as a white solid (32 mg, 90%yield). MS (apci) m/z=546.2 (M+H).

Example 558

1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((R)-2,3-dihydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared from 1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea(Example 393; 82.0 mg, 0.130 mmol) according to the procedure describedfor Example 176, to provide title compound as a white solid (67 mg, 97%yield). MS (apci) m/z=546.2 (M+H).

Example 559

1-(3-((R)-2,3-dihydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea

Prepared from1-(3-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea(Example 398; 90.0 mg, 0.149 mmol) according to the procedure describedfor Example 176, to provide title compound as a white solid (83 mg, 99%yield). MS (apci) m/z=564.2 (M+H).

Example 560

1-(3-((S)-2,3-dihydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea

Prepared from1-(3-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea (Example 399; 64.0 mg, 0.096 mmol) according to theprocedure described for Example 176, to provide title compound as awhite solid (44 mg, 81% yield). MS (apci) m/z=564.2 (M+H).

Example 561

1-(3-((S)-2-hydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea

Prepared from1-(3-((S)-2-(tert-butyldimethylsilyloxy)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea(Example 400, 64.0 mg, 0.097 mmol) according to the procedure describedfor Example 176, to provide title compound as a white solid (44 mg, 83%yield). MS (apci) m/z=548.3 (M+H).

Example 562

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((S)-2-hydroxy-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

To a solution of1-(3-((S)-2-(tert-butyldimethylsilyloxy)-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea (Example 402, 110 mg, 0.163 mmol) in THF (5 mL) wasadded 1M HCl (5 mL) and the mixture stirred at ambient temperature for90 minutes. The mixture was concentrated to 3 mL and diluted with 1M HCl(3 mL). The mixture washed with Et₂O (2×) and the aqueous solution wastreated with 50% NaOH syrup to pH=7. NaCl added to saturation and themixture was extracted with EtOAc (3×). The combined extracts were driedover MgSO₄, filtered through packed Celite® (EtOAc elution) andconcentrated to give a white solid. The solid was pulverized and driedin vacuum to furnish the title compound as a white powder (64 mg, 70%).MS (apci) m/z=560.3 (M+H).

Example 563

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((R)-2-hydroxy-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

Prepared from1-(3-((R)-2-(tert-butyldimethylsilyloxy)-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea(prepared according to the method of Example 402, 104 mg, 0.154 mmol)according to the procedure described for Example 564. The title compoundwas obtained as a white solid (76 mg, 88% yield). MS (apci) m/z=560.3(M+H).

Example 564

1-(3-((S)-2-hydroxy-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)ureaStep A:1-(3-((S)-2-(tert-butyldimethylsilyloxy)-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea

Prepared according to the procedure described for Example 1 using theappropriate starting materials. The title compound was obtained as acolorless wax (122 mg, 88% yield). MS (apci) m/z=692.3 (M+H).

Step B:1-(3-((S)-2-hydroxy-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea

To a solution of1-(3-((S)-2-(tert-butyldimethylsilyloxy)-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea(120 mg, 0.173 mmol) in THF (5 mL) was added 1M HCl (5 mL) and themixture stirred at ambient temperature for 3.5 hours. The mixture wasconcentrated to 5 mL and washed with Et₂O (3×). The aqueous solution wastreated with 50% NaOH syrup to pH=7. NaCl added to saturation andmixture extracted with EtOAc (3×). The combined extracts were dried overMgSO₄ and filtered through packed Celite®, eluting with EtOAc. Thefiltrate was concentrated and the residual white solid was washed withEt₂O (3×) and dried in vacuum to furnished the title compound (76 mg,76%). MS (apci) m/z=578.3 (M+H).

Example 565

1-(3-((R)-2-hydroxy-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)ureaStep A:1-(3-((R)-2-(tert-butyldimethylsilyloxy)-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea

Prepared according to the procedure described for Example 1 using theappropriate starting materials. The compound was obtained as a colorlesswax (131 mg, 95% yield). MS (apci) m/z=692.3 (M+H).

Step B:1-(3-((R)-2-hydroxy-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea

Utilizing1-(3-((R)-2-hydroxy-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)ureain the procedure described for Example 563, Step B, the title compoundwas obtained as a white solid (77 mg, 73%). MS (apci) m/z=578.3 (M+H).

Example 566

1-(4-bromo-1,1′-dimethyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureaStep A: phenyl 1,1′-dimethyl-1H, 1′H-3,4′-bipyrazol-5-ylcarbamate

A fine suspension of 1,1′-dimethyl-1H,1′H-3,4′-bipyrazol-5-amine(Intermediate P114, 159 mg, 0.897 mmol) in EtOAc (4 mL) was cooled to 0°C. NaOH (987 μL, 1.97 mmol) and phenylchloroformate (135 μL, 1.08 mmol)were added sequentially and the mixture was stirred for 5 minutes. Themixture was allowed to reach ambient temperature and stirred for 24hours. Mixture washed with H₂O (2×) and saturated NaCl. The solution wasdried over MgSO₄/activated carbon and was eluted through a SiO₂ plugeluting with EtOAc. The filtrate was concentrated, and the residue waswashed with hexanes (3×) and dried in vacuum to furnish the titlecompound as a colorless wax (232 mg, 87%). MS (apci) m/z=298.1 (M+H).

Step B:1-(4-bromo-1,1′-dimethyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

A solution of phenyl 1,1′-dimethyl-1H,1′H-3,4′-bipyrazol-5-ylcarbamate(44.6 mg, 0.150 mmol) in dry CH₂Cl₂ (1.0 mL) was cooled to 0° C. andN-bromosuccinimide (28.0 mg, 0.157 mmol) was added in one portion. Themixture was stirred at 0° C. for 5 minutes, allowed to reach ambienttemperature and stirred until complete consumption of starting materialwas observed by TLC analysis (16 hours). To the mixture was added(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride (Preparation F, 59.3 mg, 0.180 mmol) followed by DIEA(78.4 μL, 0.450 mmol) and the mixture stirred at ambient temperature for3 hours. The mixture was diluted with CH₂Cl₂ (3 mL) and was washed withH₂O (3×). The CH₂Cl₂ solution was dried over Na₂SO₄ and the driedsolution was eluted through a short SiO₂ column eluting with CH₂Cl₂,EtOAc and 10% (9:1 MeOH/NH₄OH)/EtOAc. The product pools were combinedand concentrated to give a colorless glass. The glass was dissolved inEtOAc and the cloudy solution and filtered through packed Celite®. Thefiltrate was concentrated and the residual white solid was washed withEt₂O and dried in vacuum to afford the title compound (57 mg, 71%). MS(apci) m/z=538.2 (M+H).

Example 567

1-(4-chloro-1,1′-dimethyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

The title compound was prepared using the procedure outlined for Example566 substituting N-bromosuccinimide with N-chlorosuccinimide in Step B.The compound was isolated as a white solid (51 mg, 69%). MS (apci)m/z=494.1 (M+H).

Example 568

1-(4-chloro-1-phenyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

A solution of phenyl1-phenyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-ylcarbamate (90.9 mg,0.250 mmol) in dry CH₂Cl₂ (1.0 mL) was treated with N-chlorosuccinimide(37.5 mg, 0.275 mmol) in one portion and the mixture was stirred atambient temperature until complete by TLC analysis (72 hours). To themixture was added(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride (Preparation F, 98.8 mg, 0.300 mmol) followed by DIEA(131 μL, 0.750 mmol) and the mixture was stirred at ambient temperaturefor 5 hours. The mixture was diluted with CH₂Cl₂ (3 mL) and was washedwith H₂O (2×), 1M NaOH (2×) and H₂O. The CH₂Cl₂ solution was dried overNa₂SO₄/activated carbon and the dried solution was filtered throughpacked Celite® and concentrated. The residue was purified on a SiO₂column using step gradient elution: 50% EtOAc-hexanes, EtOAc, and then5% MeOH/EtOAc. The combined product pools were concentrated to give acolorless syrup. The syrup was treated with 50% Et₂O-hexanes andsonicated until granular white suspension formed. The solvent wasdecanted, the solid was washed with 50% Et2O-hexanes (2×) and dried invacuum to afford the title compound as a white solid (106 mg, 76%). MS(apci) m/z=560.3 (M+H).

The compounds in the following table were prepared according to themethod of Example 568 using the appropriate phenylcarbamate andaminopyrrolidine intermediates.

Ex. # Structure Name Data 569

Tert-butyl 4-(4-chloro-5-(3- ((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)ureido)-1-phenyl-1H-pyrazol-3-yl)piperidine-1-carboxylate MS (apci) m/z = 659.3 (M + H). 570

1-(4-chloro-1-phenyl-3- (tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(4- fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea MS (apci) m/z = 542.3 (M + H). 571

1-(4-chloro-3-(3,5- dimethylisoxazol-4-yl)-1- phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3- yl)ureaMS (apci) m/z = 571.3 (M + H). 572

(R)-tert-butyl 2-(4-chloro-5-(3- ((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)ureido)-1-phenyl-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate MS (apci) m/z = 645.3 (M + H). 573

(S)-tert-butyl 2-(4-chloro-5-(3- ((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)ureido)-1-phenyl-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate MS (esi) m/z = 645.1 (M + H).

Example 574

1-(4-bromo-1-phenyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

A solution of phenyl1-phenyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-ylcarbamate (90.9 mg,0.250 mmol) in dry CH₂Cl₂ (1.0 mL) was treated with N-bromosuccinimide(53.4 mg, 0.300 mmol) in one portion and mixture was stirred at ambienttemperature until complete by TLC analysis (4 hours). To the mixture wasadded(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride (Preparation F, 98.8 mg, 0.300 mmol) followed by DIEA(131 μL, 0.750 mmol) and the mixture stirred at ambient temperature for3 hours. The mixture was diluted with CH₂Cl₂ (3 mL) and was washed withH₂O (2×), 1M NaOH (2×) and H₂O. The CH₂Cl₂ solution was dried overNa₂SO₄/activated carbon and the dried solution was filtered throughpacked Celite® and concentrated. The residue was purified on a SiO₂column eluting with a step gradient: 50% EtOAc-hexanes, EtOAc then 5%MeOH/EtOAc. The combined product pools were concentrated to give acolorless glass. The glass was dissolved in Et₂O and treated withhexanes until a suspension formed. The suspension was concentrated toprovide the title compound as a white solid that was dried in vacuum(142 mg, 94%). MS (apci) m/z=604.2 (M+H).

The compounds in the following table were prepared according to themethod of Example 574 using the appropriate phenylcarbamate andaminopyrrolidine intermediates.

MS (apci) Ex. # Structure Name m/z 575

Tert-butyl 4-(4-bromo-5-(3- ((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)ureido)-1-phenyl-1H-pyrazol-3-yl)piperidine-1- carboxylate 703.5 (M + H) 576

1-(4-bromo-1-phenyl-3- (tetrahydro-2H-pyran-4-yl)- 1H-pyrazol-5-yl)-3-((3S,4R)-4-(4- fluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3- yl)urea586.2 (M + H) 577

1-(4-bromo-3-(3,5- dimethylisoxazol-4-yl)-1- phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)urea  615.2 (M + H). 578

(R)-tert-butyl 2-(4-bromo- 5-(3-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)ureido)-1-phenyl-1H-pyrazol-3-yl)pyrrolidine-1- carboxylate 689.2 (M + H) 579

tert-butyl 4-((4-bromo-5-(3- ((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)ureido)-1-phenyl-1H- pyrazol-3-yl)methoxy)piperidine-1- carboxylate 733.2 (M + H)

Example 580

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-phenyl-3-(piperidin-4-yl)-1H-pyrazol-5-yl)ureadihydrochloride

To a solution of tert-butyl4-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazol-3-yl)piperidine-1-carboxylate(prepared according to the method of Example 569; 73 mg, 0.12 mmol) in2:1 EtOAc/MeOH (4 mL) was added 4M HCl in dioxane (3 mL) and thereaction was stirred at ambient temperature until complete by HPLCanalysis (2 hours). The mixture was concentrated and the residue wastreated with 50% EtOAc-hexanes. The mixture was sonicated until finegranular suspension formed. The solid was collected, washed with 50%EtOAc-hexanes and dried in vacuum to afford the title compound as awhite solid (70 mg, 100%). MS (apci) m/z=525.8 (M+H).

The compounds in the following table were prepared according to themethod of Example 580 using the appropriate N-Boc intermediates.

MS (apci) Ex. # Structure Name m/z 581

1-(4-chloro-1-phenyl-3- (piperidin-4-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)urea dihydrochloride 559.2 (M + H) 582

1-(4-bromo-1-phenyl-3- (piperidin-4-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)urea dihydrochloride 603.2 (M + H) 583

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-((R)- pyrrolidin-2-yl)-1H-pyrazol-5- yl)ureadihydrochloride 525.3 (M + H) 584

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-((S)- pyrrolidin-2-yl)-1H-pyrazol-5- yl)ureadihydrochloride 525.3 (M + H) 585

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(4-chloro-1-phenyl-3-((R)- pyrrolidin-2-yl)-1H-pyrazol-5- yl)ureadihydrochloride 545.2 (M + H) 586

1-((3S,4R)-4-(3,5- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-((S)- pyrrolidin-2-yl)-1H-pyrazol-5- yl)ureadihydrochloride 525.3 (M + H) 587

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(4-chloro-1-phenyl-3-((S)- pyrrolidin-2-yl)-1H-pyrazol-5- yl)ureadihydrochloride MS (esi) m/z = 545.1 (M + H) 588

1-(4-bromo-1-phenyl-3-((R)- pyrrolidin-2-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)urea dihydrochloride 589.2 (M + H) 589

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(1-phenyl-3-((piperidin-4- yloxy)methyl)-1H-pyrazol-5- yl)ureadihydrochloride 555.2 (M + H) 590

1-(4-chloro-1-phenyl-3- ((piperidin-4-yloxy)methyl)-1H-pyrazol-5-yl)-3-((3S,4R)-4- (3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea dihydrochloride 589.3 (M + H) 591

1-(4-bromo-1-phenyl-3- ((piperidin-4-yloxy)methyl)-1H-pyrazol-5-yl)-3-((3S,4R)-4- (3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3- yl)urea dihydrochloride 633.2 (M + H)

Example 592

1-(4-bromo-3-(1-(methylsulfonyl)piperidin-4-yl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

A suspension of1-(4-bromo-1-phenyl-3-(piperidin-4-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureadihydrochloride (Example 582, 70 mg, 0.103 mmol) in dry CH₂Cl₂ (1 mL)was treated with DIEA (72.1 μL, 0.414 mmol) and the mixture was stirredat ambient temperature for 5 minutes. The resulting homogeneous solutionwas cooled to 0° C. and MsCl (8.41 μL, 0.109 mmol) was added. Themixture was stirred for 2 hours during which time temperature graduallyincreased to ambient temperature. The mixture was diluted with CH₂Cl₂ (3mL) and was washed with H₂O (2×). The CH₂Cl₂ solution was dried overNa₂SO₄, filtered and concentrated. The residue was purified on SiO₂eluting with 50% EtOAc-hexanes then 5% MeOH/EtOAc. The combined productpools were concentrated and the residual colorless glass was sonicatedunder 50% Et₂O-hexanes until a granular suspension formed. The solventwas decanted and the solid dried in vacuum to afford the title compoundas a faint pink solid (54 mg, 77%). MS (apci) m/z=681.2 (M+H).

Example 593

1-(3-(1-acetylpiperidin-4-yl)-4-bromo-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

A suspension of1-(4-bromo-1-phenyl-3-(piperidin-4-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureadihydrochloride (Example 582, 71 mg, 0.105 mmol) in dry CH₂Cl₂ (1 mL)was treated with DIEA (73.3 μL, 0.420 mmol) and the mixture stirred atambient temperature for 5 minutes. The resulting homogeneous solutionwas cooled to 0° C. and Ac₂O (10.4 μL, 0.110 mmol) was added. Themixture stirred for 1 hour during which time the temperature graduallyreached 10° C. The mixture was diluted with CH₂Cl₂ (3 mL) and was washedwith H₂O (2×). The solution was dried over Na₂SO₄, filtered andconcentrated. The residue was purified on SiO₂ eluting with a stepgradient: EtOAc, 5% then 10% MeOH/EtOAc. The combined product pools wereconcentrated and the residual colorless glass was dissolved in 50%CH₂Cl₂/hexanes. The solution was concentrated to furnish the titlecompound as ivory white solid, dried in vacuum (50 mg, 74%). MS (apci)m/z=645.2 (M+H).

Example 594

1-(4-chloro-1-phenyl-3-(1-(trifluoromethylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureahydrochloride

A suspension of1-(4-chloro-1-phenyl-3-(piperidin-4-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureadihydrochloride (Example 581, 60 mg, 0.0949 mmol) in dry CH₂Cl₂ (1.5 mL)was treated with DIEA (66.3 μL, 0.380 mmol) and the mixture stirred atambient temperature for 5 minutes. The resulting homogeneous solutionwas cooled to −40° C. (dry ice, CH₃CN bath) and trifluoromethanesulfonicanhydride (17.3 μL, 0.103 mmol) was added. The mixture was stirred for 1hour during which time temp reached −5° C. The reaction mixture wasconcentrated and the residue was washed with H₂O (3× with sonication)and treated with 50% EtOAc-hexanes. The mixture was sonicated, treatedwith MgSO₄ and stirred for 30 minutes. The mixture was filtered throughpacked Celite® capped with a MgSO₄ layer using 50% EtOAc-hexanes forrinsing and elution. The filtrate was concentrated to give a colorlessfoam. The foam was dissolved in EtOAc (3 mL) and treated with 2M HCl inEt₂O (300 μL). The resulting cloudy white mixture was stirred for 5minutes and filtered through packed Celite® (EtOAc rinse). The filtratewas concentrated to provide the title compound as an ivory white solid,dried in vacuum (32 mg, 46%). MS (apci) m/z=691.2 (M+H).

Example 595

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-((R)-1-(methylsulfonyl)pyrrolidin-2-yl)-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the procedure described for Example 592 using1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-((R)-pyrrolidin-2-yl)-1H-pyrazol-5-yl)ureadihydrochloride (Example 583) to provide the title compound as a whitesolid (84 mg, 83%). MS (apci) m/z=603.3 (M+H).

Example 596

1-(3-((R)-1-acetylpyrrolidin-2-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the procedure described for Example 593 using1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-((R)-pyrrolidin-2-yl)-1H-pyrazol-5-yl)ureadihydrochloride (Example 583) to provide the title compound as an ivorywhite solid (89 mg, 94%). MS (apci) m/z=567.3 (M+H).

Example 597

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-((R)-1-methylpyrrolidin-2-yl)-1-phenyl-1H-pyrazol-5-yl)ureadihydrochloride

A solution of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-((R)-pyrrolidin-2-yl)-1H-pyrazol-5-yl)ureadihydro-chloride (Example 583, 80 mg, 0.134 mmol) and DIEA (93.5 μL,0.536 mmol) in dry CH₂Cl₂ (2 mL) was cooled to 0° C. and iodomethane(9.26 μL, 0.147 mmol) was added. The mixture was stirred for 3 hoursduring which time temperature gradually reached ambient temperature. Themixture was diluted with CH₂Cl₂ (2 mL) and H₂O (3 mL) and 1M NaOH wasadded to pH=11. The aqueous layer was removed and the CH₂Cl₂ fractionwas washed with H₂O (2×), dried over Na₂SO₄, filtered and concentrated.The residue was purified by SiO₂ chromatography using step gradientelution (EtOAc, 10% MeOH/EtOAc and 10% (9:1 MeOH/NH₄OH)/EtOAc). Thecombined product pools were concentrated to furnish the free baseproduct as a colorless wax that was dried in vacuum. The free base ofthe product was dissolved in EtOAc (3 mL) and treated with 2M HCl inEt₂O (0.4 mL). The resulting suspension was stirred for 10 minutes andwas concentrated to afford the title compound as a light tan solid thatwas dried in vacuum (25 mg, 31%). MS (apci) m/z=539.3 (M+H).

Example 598

1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-((S)-1-methylpyrrolidin-2-yl)-1-phenyl-1H-pyrazol-5-yl)ureadihydrochloride

Prepared according to the procedure described for Example 597 using1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-((S)-pyrrolidin-2-yl)-1H-pyrazol-5-yl)ureadihydrochloride (Example 586) to provide the title compound as an ivorywhite solid (31 mg, 39%). MS (apci) m/z=539.3 (M+H).

Example 599

1-(4-bromo-3-((1-(methylsulfonyl)piperidin-4-yloxy)methyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Using1-(4-bromo-1-phenyl-3-((piperidin-4-yloxy)methyl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureadihydrochloride (Example 591) in the procedure described for thesynthesis of Example 592, the title compound was obtained as a whitesolid (23 mg, 88%). MS (apci) m/z=711.2 (M+H).

Example 600

1-(3-((1-acetylpiperidin-4-yloxy)methyl)-4-bromo-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared according to the procedure described for Example 593 using1-(4-bromo-1-phenyl-3-((piperidin-4-yloxy)methyl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureadihydrochloride (Example 591) to provide the title compound a whitesolid (24 mg, 96%). MS (apci) m/z=675.2 (M+H).

Example 601

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(4-isopropyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureaStep A:5-amino-N′-isopropyl-4-methyl-1-phenyl-1H-pyrazole-3-carbohydrazide

To a solution of 5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid(Intermediate 171, 146 mg, 0.672 mmol) and DIEA (468 μL, 2.69 mmol) indry CH₂Cl₂ (3.0 mL) was added isobutyl chloroformate (98.1 μL, 0.739mmol). The mixture was stirred at ambient temperature for 1 hour and wascooled to 0° C. Isopropylhydrazine hydrochloride (149 mg, 1.34 mmol) wasadded in one portion and the mixture was stirred at ambient temperaturefor 48 hours. The mixture was washed with H₂O (2×) and dried overNa₂SO₄. The dried solution was eluted through a SiO₂ plug eluting with50% EtOAc-hexanes. The eluent was concentrated to a syrup. The syrup waswashed with hexanes and was dissolved Et₂O. The solution wasconcentrated to provide the crude title compound as an oily white solid(148 mg, 54%). MS (apci) m/z=274.1 (M+H). The crude product contained30% of the undesired regioisomer(5-amino-N-isopropyl-4-methyl-1-phenyl-1H-pyrazole-3-carbohydrazide) andwas taken directly to the next step.

Step B:5-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-3-isopropyl-1,3,4-oxadiazol-2(3H)-one

To a solution of the crude5-amino-N′-isopropyl-4-methyl-1-phenyl-1H-pyrazole-3-carbohydrazide (148mg, 0.379 mmol) in dry CH₂Cl₂ (3 mL) was added triphosgene (57.4 mg,0.190 mmol) in one portion and the resulting white suspension wasstirred for 17 hours at ambient temperature. DIEA (264 μL, 1.52 mmol)was slowly added and the resulting homogeneous solution was stirred atambient temperature for 4 hours. The mixture was washed with H₂O (3×),dried over Na₂SO₄, filtered and concentrated. The residue was purifiedon a SiO₂ column using 25% EtOAc-hexanes for elution. The product wasobtained as a white foam that was dried in vacuum (35 mg, 31%). MS(apci) m/z=300.1 (M+H).

Step C: Phenyl3-(4-isopropyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate

A solution of5-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-3-isopropyl-1,3,4-oxadiazol-2(3H)-one(30 mg, 0.100 mmol) in EtOAc (1 mL) was cooled to 0° C. NaOH (251 μL,0.501 mmol) and phenylchloroformate (37.7 μL, 0.301 mmol) were addedsequentially and the mixture was stirred for 5 minutes. The ice bath wasremoved and the mixture stirred at ambient temperature for 16 hours. Themixture was washed with H₂O (2×), 1M HCl, H₂O and saturated NaCl. Theorganic layer was diluted with 1 equal volume of hexanes and dried overMgSO₄. The solution was eluted through a SiO₂ plug eluting with 50%EtOAc-hexanes. The eluent was concentrated and the residual white solidwas washed with hexanes (3× with sonication) and dried in vacuum toprovide the title compound (28 mg, 67%). MS (apci) m/z=420.1 (M+H).

Step D:1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(4-isopropyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea

To a mixture of phenyl3-(4-isopropyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate(26 mg, 0.0620 mmol) and(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride (Preparation F, 26.5 mg, 0.0806 mmol) in CH₂Cl₂ (1 mL)was added DIEA (54.1 μL, 0.310 mmol). The resulting homogeneous solutionwas stirred at ambient temperature for 3 hours. The mixture was dilutedwith CH₂Cl₂ (2 mL) and was washed with H₂O (2×), 1M NaOH (2×) and H₂O.The CH₂Cl₂ solution was dried over Na₂SO₄, filtered and concentrated.The residue was purified on a SiO₂ column with step gradient elution:50% EtOAc/hexanes, EtOAc then 5% MeOH/EtOAc. The combined product poolswere concentrated to give a colorless glass. The glass was dissolved in1:1 CH₂Cl₂/hexanes and concentrated to afford the title compound as awhite solid, dried in vacuum (20 mg, 56%). MS (apci) m/z=582.2 (M+H).

Example 602

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1-phenyl-1H-pyrazol-5-yl)ureaStep A: tert-butyl2-(5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carbonyl)-1-methylhydrazinecarboxylate

To a fine suspension of5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid (Intermediate171, 0.434 g, 2.00 mmol) in dry CH₂Cl₂ (5 mL) was added DIEA (0.766 mL,4.40 mmol) and the mixture was stirred at ambient temperature for 5minutes. The resulting solution was treated with isobutyl chloroformate(0.292 mL, 2.20 mmol) and the mixture was stirred for 2 hours.Tert-butyl 1-methylhydrazinecarboxylate (0.308 mL, 2.00 mmol) was addedand the mixture stirred at ambient temperature for 23 hours. The mixturewas washed with H₂O (2×), dried over Na₂SO₄, and the dried CH₂Cl₂solution was eluted through a SiO₂ plug (50% EtOAc-hexanes for elution).The eluent was concentrated a colorless waxy solid. The solid wastreated with 50% Et₂O-hexanes and stirred until a granular whitesuspension formed. The solvent was decanted, the residual solid waswashed with 50% Et₂O-hexanes and dried in vacuum provide the titlecompound as a white powder (550 mg, 80%). MS (apci) m/z=346.2 (M+H).

Step B: 5-amino-N′,4-dimethyl-1-phenyl-1H-pyrazole-3-carbohydrazidedihydrochloride

To a solution of tert-butyl2-(5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carbonyl)-1-methylhydrazinecarboxylate(540 mg, 1.56 mmol) in EtOAc (10 mL) was added 4M HCl (7.82 mL, 31.3mmol) in dioxane and the mixture was stirred at ambient temperature for17 hours. The resulting white suspension was concentrated and theresidual white solid was dried in vacuum to provide the title compound(490 mg, 99%). MS (apci) m/z=246.1 (M+H). ¹H NMR (DMSO d₆) δ 11.6 (br s,2H), 11.3 (s, 1H), 7.63 (d, 2H), 7.54 (t, 2H), 7.44 (t, 1H), 2.82 (s,3H), 2.13 (s, 3H).

Step C:5-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one

A solution of5-amino-N′,4-dimethyl-1-phenyl-1H-pyrazole-3-carbohydrazidedihydrochloride (484 mg, 1.52 mmol) and DIEA (1.32 mL, 7.61 mmol) in dryCH₂Cl₂ (10 mL) was cooled to 0° C. and triphosgene (230 mg, 0.761 mmol)was added in one portion. The mixture stirred for 17 hours during whichtime temperature reached ambient temperature after 2 hours. AdditionalDIEA (0.40 mL), was added and the mixture was stirred for an 5 hours.The mixture was washed with H₂O (3×), dried over Na₂SO₄ and the driedsolution was eluted through a short SiO₂ column eluting 25%EtOAc-hexanes. The eluent was concentrated and the residual waxy solidwas treated with 50% Et₂O-hexanes and stirred until a fine, granularsuspension formed. The solvent was decanted and the residual solid waswashed with 50% Et₂O-hexanes (2×) and dried in vacuum to afford thetitle compound as a ivory white solid (197 mg, 48%). MS (apci) m/z=272.1(M+H).

Step D: Phenyl4-methyl-3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate

Using5-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-onein the procedure described for the preparation of Example 601, Step Cprovided the title compound as a white solid (80 mg, 59%). MS (apci)m/z=272.1 (aminopyrazole fragment M+H).

Step E:1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1-phenyl-1H-pyrazol-5-yl)urea

Prepared according to the method of Example 601, Step D, using Phenyl4-methyl-3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate.The title compound was isolated as a white solid (50 mg, 60%). MS (apci)m/z=554.2 (M+H).

Example 603

1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(pyrazin-2-yloxy)-1H-pyrazol-5-yl)ureaStep A: 4-methyl-1-phenyl-3-(pyrazin-2-yloxy)-1H-pyrazol-5-amine

In a sealed tube were combined5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (Preparation P135, StepA, 300 mg, 1.59 mmol), 2-chloropyrazine (185 mg, 1.59 mmol), CuCN (14.2mg, 0.159 mmol), cesium carbonate (620 mg, 1.90 mmol) and dry DMF (3.2mL). Ethylenediamine (23.3 μL, 0.349 mmol) was added and the vessel wasflushed with N₂ and sealed. The mixture was stirred at 110° C. for 18hours and was cooled to ambient temperature. The mixture was added toice-H₂O (30 mL) and was stirred for 10 minutes. The mixture wasextracted with EtOAc (3×) and the combined organic fractions were washedwith saturated NaCl (2×), dried over MgSO₄ filtered through packedCelite®. The filtrate was concentrated and the residual syrup waspurified on a SiO₂ column eluting with 40% EtOAc-hexanes to provide thetitle compound as a white solid (310 mg, 73%). MS (apci) m/z=268.0(M+H). ¹H NMR (CDCl₃) δ 8.54 (s, 1H), 8.28 (s, 1H), 8.16 (s, 1H), 7.58(d, 2H), 7.44 (t, 2H), 7.31 (t, 1H), 3.74 (br s, 2H), 1.81 (s, 3H).

Step B:1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(pyrazin-2-yloxy)-1H-pyrazol-5-yl)urea

To a solution of4-methyl-1-phenyl-3-(pyrazin-2-yloxy)-1H-pyrazol-5-amine (50.0 mg, 0.187mmol) in dry DMF (1.0 mL) was added CDI (36.4 mg, 0.224 mmol) and DIEA(49.0 μL, 0.281 mmol). The mixture was stirred at ambient temperaturefor 16 hours. Additional CDI (31 mg) was added and the mixture stirredfor 24 hours. To the mixture was added(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine(Preparation L1, 98.1 mg, 0.412 mmol) and the mixture was stirred atambient temperature for 5 hours. The mixture was diluted with chilledH₂O (4 mL) and the resulting milky suspension was treated with 2M HCl topH=7 (starting pH=1). The mixture was extracted with EtOAc (3×) and thecombined EtOAc fractions were washed with saturated NaCl (3×). The EtOAcsolution was dried over MgSO₄, filtered through packed Celite® andconcentrated. The residual colorless glass was purified on a SiO₂ columnwith step gradient elution (EtOAc, 5% MeOH/EtOAc, 10% (9:1CH₃OH/NH₄OH)/EtOAc). The resulting white foam was recrystallized from50% EtOAc-hexanes to furnish the title compound as white spheres thatwere crushed and dried in vacuum (44 mg, 44%). MS (apci) m/z=532.2(M+H).

Example 604

1-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)-3-(4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)urea

A solution of triphosgene (23.1 mg, 0.074 mmol) in dry CH₃CN (1 mL) wascooled to 0° C. and a solution of(3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-aminedihydrochloride (Preparation M, 76.4 mg, 0.220 mmol) and DIEA (115 μL,0.660 mmol) in dry CH₃CN (0.5 mL) was added over 45 minutes. The mixturewas stirred for 1 hour during which time the temperature reached 15° C.5-(5-Amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-1-methylpyridin-2(1H)-one(56.1 mg, 0.200 mmol) was added in one portion and the mixture stirredat ambient temperature for 7 hours followed by stirring at 40° C. for 17hours. The mixture was cooled to ambient temperature and was dilutedwith chilled H₂O (4 mL). The cold mixture (pH=5) was treated with 2MNaOH to pH=10. The mixture was extracted with EtOAc (3×) and thecombined extracts were washed with H₂O and saturated NaCl (2×). TheEtOAc solution was dried over MgSO₄ and eluted through a short SiO₂column eluting with EtOAc, 10% MeOH/EtOAc then 10%(9:1/CH₃OH—NH₄OH)/EtOAc. The combined product pools were concentrated.The residue was treated with Et₂O and agitated until a white suspensionformed. The solvent was decanted and the remaining solid was washed withEt₂O (2×) and dried in vacuum to provide the title compound as a whitesolid (34 mg, 29%). MS (apci) m/z=581.2 (M+H).

Example 605

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-methoxy-1-phenyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)ureaStep A: Preparation of5-fluoro-3-methoxy-1-phenyl-4-(trifluoromethyl)-1H-pyrazole

A mixture of NEt₃ (0.657 mL, 4.72 mmol) and phenylhydrazine (0.561 g,5.19 mmol) in EtOH (2 mL) was added dropwise to a solution of1,3,3,3-tetrafluoro-1-methoxy-2-(trifluoromethyl)prop-1-ene (1.00 g,4.72 mmol) in EtOH (3 mL). After the addition was complete, the reactionwas stirred at ambient temperature overnight, concentrated and purifiedby silica gel column chromatography, eluting with 0-10% EtOAc/hexanes toafford the tile compound (372 mg, 1.43 mmol, 30.3% yield). MS (apci)m/z=261.1 (M+H).

Step B: Preparation of3-methoxy-1-phenyl-4-(trifluoromethyl)-1H-pyrazol-5-amine

5-fluoro-3-methoxy-1-phenyl-4-(trifluoromethyl)-1H-pyrazole (400 mg,1.54 mmol), hydrazine (148 mg, 4.61 mmol) and NEt₃ (643 μL, 4.61 mmol)were combined in DME (3 mL) in a sealed vessel and heated in a 90° C.sand bath for 3 hours. The reaction was cooled and Raney Nickel (132 mg,1.54 mmol) added. The reaction was stirred at ambient temperature for 3hours, filtered through Celite®, concentrated and purified byreverse-phase column chromatography, eluting with 0-80%acetonitrile/water, to afford the title compound (322 mg, 1.25 mmol,81.4% yield). MS (apci) m/z=258.1 (M+H).

Step C: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)-pyrrolidin-3-yl)-3-(3-methoxy-1-phenyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)urea

3-methoxy-1-phenyl-4-(trifluoromethyl)-1H-pyrazol-5-amine (77 mg, 0.2994mmol), CDI (50.97 mg, 0.3143 mmol) and DIEA (521.4 μL, 2.994 mmol) werecombined in 0.8 mL of DMF and stirred ambient temperature overnight. 0.6mL of the resultant solution were then added to(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydro-chloride (60 mg, 0.18 mmol) and the mixture was stirred atambient temperature for 2 hours, loaded onto a samplet and purified byreverse-phase column chromatography, eluting with 5-80%acetonitrile/water, to afford the title compound (40 mg, 0.074 mmol, 52%yield). (MS (apci) m/z=540.2 (M+H).

Example 606

1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-methoxy-1-phenyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)urea

Prepared by the method as described in Example 605, Step C, using(3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride instead of(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride. The material was purified by reverse-phase columnchromatography using 5-80% acetonitrile/H₂O as the eluent to provide thetitle compound (11 mg, 0.021 mmol, 30% yield). MS (apci) m/z=540.2(M+H).

Example 607

1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-methoxy-1-phenyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)urea

Prepared by the method as described in Example 605, Step C using(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride instead of(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride. The material was purified by reverse-phase columnchromatography using 5-80% acetonitrile/H₂O as the eluent to provide thetitle compound (22 mg, 0.042 mmol, 60% yield). MS (apci) m/z=522.2(M+H).

Example 608

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-methoxy-1-phenyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)ureaStep A: Preparation of2-methyl-3-(1-methyl-1H-imidazol-4-yl)-3-oxopropanenitrile

Propiononitrile (0.893 g, 16.2 mmol) was added dropwise to a 1M solutionof LHMDS (13.0 mL, 13.0 mmol) in THF at −78° C. The mixture was stirredfor 30 minutes and a solution of ethyl1-methyl-1H-imidazole-4-carboxylate (1.00 g, 6.49 mmol) in THF (20 mL,heated to dissolve the starting material) was added dropwise. Thereaction was allowed to warm to ambient temperature, stirred overnight,poured into ice water (50 mL) and extracted with EtOAc (100 mL). The pHwas adjusted to 6.5 using 2N HCl and the mixture was extracted withEtOAc (100 mL). The pH was then adjusted to 6 using 2N HCl and themixture was extracted with EtOAc (2×100 mL). The combined extracts fromthe pH 6.5 and pH 6 extractions were dried (MgSO₄), filtered andconcentrated to provide the title compound (1.02 g, 6.25 mmol, 96.4%yield). MS (apci) m/z=164.2 (M+H).

Step B: Preparation of4-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-phenyl-1H-pyrazol-5-aminehydrochloride

A pressure vessel was charged with2-methyl-3-(1-methyl-1H-imidazol-4-yl)-3-oxopropanenitrile (1.00 g, 6.13mmol), absolute EtOH (12.3 mL, 6.13 mmol) and phenylhydrazinehydrochloride (0.975 g, 6.74 mmol). The reaction was sealed, heated at80° C. overnight and concentrated to afford the title compound (1.70 g,5.87 mmol, 95.7% yield). MS (apci) m/z=254.1 (M+H).

Step C: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-phenyl-1H-pyrazol-5-yl)urea

4-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-phenyl-1H-pyrazol-5-amine (20mg, 0.07896 mmol) was dissolved in 2 mL of EtOAc and NaOH (789.6 μL,0.7896 mmol) was added followed by phenylchloroformate (29.72 μL, 0.2369mmol). The reaction was stirred at ambient temperature overnight, 10 mLof EtOAc were added and the organic layer was washed with Brine, dried(MgSO₄), concentrated and taken up in CH₂Cl₂ (1 mL).(3S,4R)-4-(3,4-Difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride (20 mg, 0.061 mmol) and DIEA (88 μL, 0.51 mmol) wereadded and the reaction was stirred at ambient temperature overnight,concentrated and purified reverse-phase column chromatography, elutingwith 0-70% acetonitrile/water, to afford the title compound (2.4 mg,0.0045 mmol, 8.9% yield). (MS (apci) m/z=536.2 (M+H).

Example 609

1-((trans)-4-(4-chloro-3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-5-oxo-2-phenyl-2,5-dihydro-1H-pyrazol-3-yl)urea

CDI (360 mg, 2.22 mmol), 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one(350 mg, 1.85 mmol) and DIEA (805 μL, 4.62 mmol) were combined in 3 mLof DMF and stirred at ambient temperature overnight. Additional CDI (360mg, 2.22 mmol) was added and the reaction stirred at ambient temperaturefor 24 hours. 0.2 mL of the resultant solution were added to a solutionof(trans)-4-(4-chloro-3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydro-chloride (67.5 mg, 0.195 mmol) and DIEA (80.9 μl, 0.465 mmol) inDMF (2 mL) and stirred at ambient temperature for 3 hours. The reactionwas loaded onto a samplet and purified reverse-phase columnchromatography, eluting with 0-70% acetonitrile/water, to afford thetitle compound (39 mg, 0.0799 mmol, 86.0% yield). (MS (apci) m/z=488.1(M+H).

The following compounds were prepared according to the method of Example609, replacing(3S,4R)-4-(4-chloro-3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydro-chloride with the appropriate pyrrolidine intermediate.

Ex. # Structure Name MS (apci) m/z 610

1-((trans)-4-(3-chloro-4- fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-5- oxo-2-phenyl-2,5-dihydro-1H-pyrazol-3-yl)urea 488.2 (M + H) 611

1-((3S,4R)-4-(3,5- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (4-methyl-5-oxo-2-phenyl-2,5-dihydro-1H-pyrazol-3-yl)urea 472.2 (M + H) 612

1-((3S,4R)-1-(2-methoxyethyl)-4- (3,4,5-trifluorophenyl)pyrrolidin-3-yl)-3-(4-methyl-5-oxo-2-phenyl- 2,5-dihydro-1H-pyrazol-3-yl)urea 490.2(M + H) 613

1-((3S,4R)-4-(3-fluorophenyl)-1- (2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-5-oxo-2-phenyl-2,5- dihydro-1H-pyrazol-3-yl)urea 454.2 (M +H) 614

1-((trans)-4-(3-chloro-5- fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (4-methyl-5-oxo-2-phenyl-2,5-dihydro-1H-pyrazol-3-yl)urea 488.2 (M + H)

Example 615

1-(4-cyano-3-methoxy-1-phenyl-H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureaStep A: Preparation of5-amino-3-methoxy-1-phenyl-1H-pyrazole-4-carbonitrile

To a solution of phenylhydrazine (0.783 g, 7.24 mmol) in ethanol (5 mL)in a pressure tube was added 2-(dimethoxymethylene)malononitrile (1.0 g,7.24 mmol). The mixture was heated to 100° C. for 18 hours. The solventwas evaporated and the crude product was purified by silica gel columnchromatography, eluting with 5-35% acetone/hexanes to afford the titlecompound (708 mg, 45.6% yield). MS (apci) m/z=215.1 (M+H).

Step B: Preparation of1-(4-cyano-3-methoxy-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

5-amino-3-methoxy-1-phenyl-1H-pyrazole-4-carbonitrile (160 mg, 0.747mmol), CDI (133 mg, 0.822 mmol) and DIEA (650 μL, 3.73 mmol) werecombined in 5 mL of DMF and stirred at ambient temperature for 3 days.(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride (295 mg, 0.896 mmol) was added and the reaction wasstirred at ambient temperature for 1 hour, loaded onto a samplet andpurified by reverse-phase column chromatography, eluting with 0-70%acetonitrile/water, to afford the title compound (328 mg, 0.661 mmol,88.4% yield). MS (apci) m/z=497.2 (M+H).

Example 616

1-((3S,4R)-4-(3-chloro-5-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-5-oxo-2-phenyl-2,5-dihydro-1H-pyrazol-3-yl)urea

Prepared as described in Example 615, Step B, substituting5-amino-3-ethyl-1-phenyl-1H-pyrazole-4-carbonitrile for5-amino-3-methoxy-1-phenyl-1H-pyrazole-4-carbonitrile. The material waspurified by reverse-phase column chromatography using 0-70%acetonitrile/H₂O as the eluent to provide the title compound (890 mg,1.80 mmol, 76.4% yield). MS (apci) m/z=495.2 (M+H).

Example 617

1-(4-cyano-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

Prepared as described in Example 615, Step B, substituting5-amino-1-phenyl-3-(trifluoromethyl)-1H-pyrazole-4-carbonitrile for5-amino-3-methoxy-1-phenyl-1H-pyrazole-4-carbonitrile. The material waspurified by reverse-phase column chromatography using 0-70%acetonitrile/H₂O as the eluent to provide the title compound (0.81 g,1.52 mmol, 76.4% yield). MS (apci) m/z=535.2 (M+H).

Example 618

1-(4-cyano-5-oxo-2-phenyl-2,5-dihydro-1H-pyrazol-3-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea

1-(4-cyano-3-methoxy-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea(30 mg, 0.06042 mmol, prepared as described in Example 615) was taken upin HCl (61.20 mg, 0.6042 mmol) and stirred at ambient temperature fortwo days. The reaction was poured into 2N NaOH (5 mL) and extracted withEtOAc (2×25 mL). The combined organic extracts were dried (MgSO₄),concentrated and purified by reverse-phase column chromatography using0-70% acetonitrile/H2O as the eluent. Peak 1 was isolated to provide thetitle compound (11 mg, 0.02280 mmol, 37.73% yield). MS (apci) m/z=483.2(M+H).

Example 619

5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-3-methoxy-1-phenyl-1H-pyrazole-4-carboxamide

Prepared as described in Example 618, isolating peak 2 instead of peak 1to provide the title compound (1.9 mg, 0.0037 mmol, 6.1% yield). MS(apci) m/z=515.2 (M+H).

The following compounds were prepared according to the method of Example618, replacing 5-amino-3-methoxy-1-phenyl-1H-pyrazole-4-carbonitrilewith the appropriate carbonitrile, and for Examples 623-626, alsoreplacing(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride with the appropriate pyrrolidine intermediate.

MS (apci) Ex. # Structure Name m/z 620

5-(3-((3S,4R)-4-(3,4-difluoro-phenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-3-methyl-1-phenyl-1H- pyrazole-4-carboxamide 499.2 (M + H)621

5-(3-((3S,4R)-4-(3,4-difluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-3-ethyl-1-phenyl-1H- pyrazole-4-carboxamide 513.2 (M + H) 622

5-(3-((3S,4R)-4-(3,4-difluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-3- (trifluoromethyl)-1H-pyrazole-4- carboxamide553.2 (M + H) 623

5-(3-((trans)-4-(3-chloro-4- fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)- 3-methyl-1-phenyl-1H-pyrazole-4-carboxamide 515.2 (M + H) 624

5-(3-((trans)-4-(4-chloro-3- fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)- 3-methyl-1-phenyl-1H-pyrazole-4-carboxamide 515.2 (M + H) 625

5-(3-((trans)-4-(3-chloro-5- fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)- 3-methyl-1-phenyl-1H-pyrazole-4-carboxamide 515.2 (M + H) 626

5-(3-((3S,4R)-4-(3,5-difluorophenyl)- 1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-3-methyl-1-phenyl-1H- pyrazole-4-carboxamide 499.2 (M + H)

Example 627

5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazole-4-carboxamideStep A: Activation of 5-amino-1-phenyl-1H-pyrazole-4-carboxamide

5-amino-1-phenyl-1H-pyrazole-4-carboxamide (500 mg, 2.47 mmol) wasdissolved in 2 mL of CHCl₃ and pyridine (600 μL, 7.42 mmol) was addedfollowed by phenylchloroformate (682 μL, 5.44 mmol). The reaction wasstirred at ambient temperature for 2 hours and quenched with 2 mL of 2NNaOH. The reaction was extracted with several portions of CH₂Cl₂ in aphase separator frit and the combined organic extracts wereconcentrated. The crude material was purified by silica gel columnchromatography, eluting with 5-40% acetone/hexanes to afford abis-phenylcarbamate adduct (191 mg, 0.432 mmol, 17.5% yield). MS (apci)m/z=443.1 (M+H).

Step B: Preparation of5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazole-4-carboxamide

(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride (33 mg, 0.099 mmol), the product of step A (20 mg, 0.045mmol) and DIEA (39 μL, 0.23 mmol) were combined in 0.2 mL of DMF andstirred ambient temperature overnight. The mixture was loaded onto asamplet and purified by reverse-phase column chromatography using 0-70%acetonitrile/H2O as the eluent to provide the title compound (17 mg,0.035 mmol, 78% yield). MS (apci) m/z=485.2 (M+H).

Example 628

5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazole-4-carboxamideStep A: Preparation of 2-(2,2-difluoro-1-hydroxyethylidene)malononitrile

A solution of malononitrile (4 g, 61 mmol) in methanol was charged withsodium methoxide (14 g, 67 mmol) followed by methyl 2,2-difluoroacetate(8.0 g, 73 mmol). The reaction was heated to 60° C. for 4 hours andconcentrated in vacuo to afford the title compound (8.7 g, 60 mmol, 100%yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 6.13 (t, J=54 Hz, 1H).

Step B: Preparation of 2-(1-chloro-2,2-difluoroethylidene)malononitrile

To a slurry of 2-(2,2-difluoro-1-hydroxyethylidene)malononitrile (1.9 g,13 mmol) in CH₂Cl₂ was added PCl₅ (2.7 g, 13 mmol) and the reaction wasstirred at ambient temperature for 16 hours. The reaction was dilutedwith CH₂Cl₂, washed with water and brine, dried over MgSO4 andconcentrated to provide the title compound (2.3 g, 14 mmol, 107% yield).

Step C: Preparation of5-amino-3-(difluoromethyl)-1-phenyl-1H-pyrazole-4-carbonitrile

To a solution of 2-(1-chloro-2,2-difluoroethylidene)malononitrile inethanol was added phenylhydrazine hydrochloride (2.3 g, 16 mmol) and thereaction was heated to 70° C. for 4 hours. The reaction was concentratedin vacuo and the material was partitioned between EtOAc and water. Thelayers were separated and the organic layer was washed with brine, dried(MgSO₄) and concentrated in vacuo. The crude material was purified bysilica gel column chromatography using 5% EtOAc/CH₂Cl₂ as the eluent toprovide the title compound (0.25 g, 1.1 mmol, 7.5% yield). MS (apci)m/z=233.1 (M−H).

Step D: Preparation of3-(difluoromethyl)-5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazole-4-carbox-amide

5-amino-3-(difluoromethyl)-1-phenyl-1H-pyrazole-4-carbonitrile waselaborated as described for5-amino-3-methoxy-1-phenyl-1H-pyrazole-4-carbonitrile in Example 618.The material was purified by reverse-phase column chromatography using5-80% acetonitrile/H₂O as the eluent followed by Gilson preparative HPLCusing a Chiral Technologies OD-H column and hexanes/EtOH 9:1 as theeluent to provide the title compound (1.7 mg, 0.0032 mmol, 0.30% yieldfor two steps). MS (apci) m/z=533.2 (M−H).

Example 629

1-(4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)guanidinedihydrochloride

1-(4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)thiourea(40 mg, 0.07267 mmol, prepared by the method described in Example 630)and AgOTf (46.68 mg, 0.1817 mmol) were combined in 5 mL of CH₂Cl₂ andcooled in an ice-MeOH bath. Ammonia gas was bubbled through the solutionfor 1 minute and the reaction was allowed to warm to ambienttemperature. HCl (5N in IPA, 60.7 μL, 0.303 mmol) and MeOH (2 mL) wereadded and the reaction was filtered through Celite®. The solids werewashed with several portions of MeOH and the combined filtrate wasconcentrated and purified by reverse-phase column chromatography using0-70% acetonitrile/0.1N aqueous HCl as the eluent to provide the titlecompound (11 mg, 0.01814 mmol, 24.97% yield). MS (apci) m/z=535.1 (M+H).

Example 630

1-(4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)thiourea

4-Bromo-3-methyl-1-phenyl-1H-pyrazol-5-amine (250 mg, 0.992 mmol), DIEA(864 μL, 4.96 mmol) and di(1H-imidazol-1-yl)methanethione (177 mg, 0.992mmol) were combined in 1 mL of DMF and stirred at ambient temperaturefor 3 days and then at 70° C. overnight.(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride (326 mg, 0.992 mmol) was added and the reaction wasstirred at ambient temperature for 24 hours. The mixture was loaded ontoa samplet and purified by reverse-phase column chromatography using5-80% acetonitrile/H₂O as the eluent to provide the title compound (364mg, 0.661 mmol, 66.7% yield). MS (apci) m/z=550.1 (M+H).

Example 631

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)thiourea

Prepared as described for Example 630, substituting5-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-1-methylpyridin-2(1H)-onefor 4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-amine. The material waspurified by reverse-phase column chromatography using 5-80%acetonitrile/H₂O as the eluent to provide the title compound (4.5 mg,0.00778 mmol, 12.5% yield). MS (apci) m/z=579.2 (M+H).

Example 632

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)thiourea

Prepared as described for Example 630, substituting1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-amine for4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-amine. The material was purifiedby reverse-phase column chromatography using 5-80% acetonitrile/H₂O asthe eluent to provide the title compound (71 mg, 0.129 mmol, 75.8%yield). MS (apci) m/z=552.2 (M+H).

Example 633

1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)thiourea

Prepared as described for Example 630, substituting1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-amine for4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-amine and(3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride for(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride. The material was purified by reverse-phase columnchromatography using 5-80% acetonitrile/H₂O as the eluent to provide thetitle compound (50 mg, 0.0937 mmol, 69.0% yield). MS (apci) m/z=534.2(M+H).

The compounds of were prepared according to the method of Example 52using the appropriate starting materials in a suitable solvent such asCH₂Cl₂, DMF, DMA or CH₃CN.

Ex. # Structure Name Data 634

Trans-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)-3-(2-phenylpyrazolo[1,5-a]pyridin- 3-yl)urea MS (apci) m/z = 456.3 (M + H)635

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(2-phenylpyrazolo[1,5- a]pyridin-3-yl)urea MS (apci) m/z = 492.0 (M +H) 636

Trans-1-(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)-3-(pyrazolo[1,5-a]pyridin-3- yl)urea MS (apci) m/z = 380.2 (M + H) 637

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(pyrazolo[1,5-a]pyridin-3- yl)urea MS (apci) m/z = 416.1 (M + H) 638

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2- methoxyethyl)pyrrolidin-3-yl)-3-(5-methyl-3-phenyl-1- (pyrazin-2-yl)-1H-pyrazol-4- yl)urea MS (esi)m/z = 534.2 (M + H)

The following compounds were prepared according to the method of Example1 using the appropriate starting materials in a suitable solvent such asCH₂Cl₂, DMF, DMA or CH₃CN.

Ex. # Structure Name MS (apci) m/z 639

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (1,5-dimethyl-3-phenyl-1H-pyrazol-4-yl)urea 470.2 (M + H) 640

1-((3S,4R)-4-(3,5- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (1,5-dimethyl-3-phenyl-1H-pyrazol-4-yl)urea 470.2 (M + H) 641

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (1-isopropyl-5-methyl-3-phenyl-1H-pyrazol-4-yl)urea 498.2 (M + H) 642

1-((3S,4R)-4-(3,5- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (1-isopropyl-5-methyl-3-phenyl-1H-pyrazol-4-yl)urea 498.2 (M + H) 643

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (5-methyl-3-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4- yl)urea 538.2 (M + H) 644

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (1-ethyl-5-methyl-3-phenyl-1H-pyrazol-4-yl)urea 484.2 (M + H) 645

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (1-ethyl-3-methyl-5-phenyl-1H-pyrazol-4-yl)urea 484.3 (M + H) 646

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (1-methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4- yl)urea 524.2 (M + H) 647

1-((3S,4R)-4-(3,4- difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (1-methyl-3-phenyl-5-(trifluoromethyl)-1H-pyrazol-4- yl)urea 524.2 (M + H)

Example 648

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-methyl-1-phenyl-1H-pyrazol-4-yl)ureaStep A: Preparation of ethyl 3-methyl-1-phenyl-1H-pyrazole-4-carboxylate

A mixture of ethyl 3-methyl-1H-pyrazole-4-carboxylate (0.600 g, 3.89mmol), phenylboronic acid (0.498 g, 4.09 mmol), Cu(OAc)₂ (0.530 g, 2.92mmol), pyridine (0.630 mL, 7.78 mmol) in dry DMF (39 mL) was stirred atambient temperature for 3 days. The reaction mixture was partitionedbetween EtOAc and water and the organic layer was removed. The aqueouslayer was extracted with EtOAc (2×) and the combined organic layers werewashed with water and saturated NaCl. The EtOAc solution was dried overMgSO₄, filtered and concentrated. The residue was purified by flashchromatography on silica gel (4:1 hexanes/EtOAc) to give the titlecompound (0.428 g, 48%). MS (apci) m/z=231.1 (M+H).

Step B: Preparation of 3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid

To a solution of ethyl 3-methyl-1-phenyl-1H-pyrazole-4-carboxylate(0.428 g, 1.86 mmol) in 1:1 MeOH/THF (8.0 mL) was added 1M LiOH (3.72mL, 3.72 mmol) and the mixture was stirred at ambient temperature for 16hours. The solvents were removed in vacuum, the residue was diluted withwater and was extracted with Et₂O (2×). The aqueous layer was treatedwith 1M HCl to pH 4-5 and was extracted with EtOAc (3×). The combinedorganic fractions were washed with water and saturated NaCl. The EtOAcsolution was dried over MgSO4, filtered and concentrated to provide thecrude product (0.280 g, 75%) that was used in the next step withoutfurther purification. MS (apci) m/z=203.1 (M+H).

Step C: Preparation of1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxy-ethyl)pyrrolidin-3-yl)-3-(3-methyl-1-phenyl-1H-pyrazol-4-yl)urea

To a solution of 3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (50 mg,0.25 mmol) and Et₃N (0.039 mL, 0.30 mmol) in toluene (2 mL) was addeddiphenyl phosphorazidate (0.064 mL, 0.30 mmol). The solution was heatedat reflux for 1 hour and was cooled to ambient temperature. The mixturewas diluted with THF (1 mL) and(3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-aminedihydrochloride (98 mg, 0.30 mmol) was added followed by and Et₃N (0.108mL, 0.90 mmol). The reaction mixture was stirred at ambient temperaturefor 16 hours. The mixture was partitioned between EtOAc and saturatedaqueous NaHCO₃. The organic layer was removed and the aqueous layer wasextracted with EtOAc (2×). The combined organic layers were washed withsaturated NaCl, dried over MgSO₄, filtered and concentrated. The residuewas purified by flash chromatography on silica gel (5% MeOH/DCM) to givethe title compound (66 mg, 59%). MS (apci) m/z=456.2 (M+H).

Example 649

1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)urea

Prepared according to the procedure described for Example 648, Step C,using 1-phenyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid as areplacement for 3-methyl-1-phenyl-1H-pyrazole-4-carboxylic. MS (apci)m/z=510.2 (M+H).

The invention claimed is:
 1. A compound having the formula II

wherein: the Y—B moiety and the NH₂ moiety are in the transconfiguration; R^(a), R^(b), R^(c) and R^(d) are independently selectedfrom H and (1-3C)alkyl; R¹ is (1-3C alkoxy)(1-6C)alkyldifluoro(1-6C)alkyl, or trifluoro(1-6C)alkyl; R² is H, F, or OH; Y is abond; B is Ar¹, or hetAr¹; Ar¹ is phenyl optionally substituted with oneor more substituents independently selected from halogen, CF₃, CF₃O—,(1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-6C)alkyl and CN; and hetAr¹ is a5-6 membered heteroaryl having 1-3 ring heteroatoms independentlyselected from N, S and O, and optionally substituted with 1-2 groupsindependently selected form (1-6C)alkyl, halogen, OH, CF₃, NH₂ andhydroxy(1-2C)alkyl.
 2. A compound according to claim 1, wherein R¹ is(1-3C alkoxy)(1-6C)alkyl.
 3. A compound according to claim 1, wherein Bis Ar¹.
 4. A compound according to claim 3, wherein Ar¹ is phenyloptionally substituted with one or more halogens.
 5. A compoundaccording to claim 1, wherein B is hetAr¹.
 6. A compound according toclaim 5, wherein hetAr¹ is pyridyl optionally substituted with 1-2groups independently selected from (1-6C)alkyl or halogen.
 7. A compoundaccording to claim 1, wherein R² is H.
 8. A compound according to claim1, wherein R^(a), R^(b), R^(c) and R^(d) are H.
 9. A compound accordingto claim 3, wherein Ar¹ is phenyl optionally substituted with one ormore groups independently selected from halogen, CN and CF₃.
 10. Acompound according to claim 1, selected from: